JP5889875B2 - Azaindazole - Google Patents

Description

  The present invention relates to substituted azaindazoles that are useful for inhibiting EZH2, thereby inhibiting proliferation in cancer cells and / or inducing apoptosis.

  The present invention relates to substituted azaindazoles that are useful for inhibiting EZH2, thereby inhibiting proliferation in cancer cells and / or inducing apoptosis. A wide range of epigenetic modifications are common in cancer and include a wide range of changes in DNA and / or histone methylation, aberrant regulation of non-coding RNA and nucleosome remodeling, and aberrant activity of oncogenes, tumor suppressors and signaling pathway Cause inactivation or inactivation. However, unlike genetic mutations that occur in cancer, these epigenetic changes can be reversed through selective inhibition of related enzymes. Several methylases involved in histone or DNA methylation are known to be dysregulated in cancer. Thus, selective inhibitors of certain methylases appear to be useful for proliferative diseases such as cancer.

  EZH2 (enhancer of zest homolog 2; human EZH2 gene: Cardoso, C, et al; European J of Human Genetics, Vol. 8, No. 3 Pages 174-180, 2000) trimethylates lysine 27 of histone H3 (H3K27me3) is a catalytic subunit of Polycomb Repressor Complex 2 (PRC2) having a function of silencing a target gene. Histone H3 is one of five major histone proteins involved in chromatin structure in eukaryotic cells. With a globular major domain and a long N-terminal tail, histones are involved in the “beads on a string” structure, the structure of nucleosomes. Histone proteins are highly post-translationally modified, but histone H3 is the most widely modified of the five histones. The term “histone H3” is intentionally ambiguous by itself in that it does not distinguish between sequence variants or modified states. Histone H3 is an important protein in the emerging field of epigenetics, where its sequence variation and various modification states are thought to play a role in the dynamic and long-term regulation of genes.

  Increased EZH2 expression has been observed in many solid tumors including prostate, breast, skin, bladder, liver, pancreas, head and neck solid tumors and correlates with cancer pathogenicity, metastasis and poor outcome (Varambally et al., 2002; Kleer et al., 2003; Breuer et al., 2004; Bachmann et al., 2005; Weikert et al., 2005; Sudo et al., 2005; Bachmann et al., 2006). For example, tumors expressing high levels of EZH2 have a greater risk of recurrence after prostatectomy, increased metastasis, short disease-free survival, and increased mortality in breast cancer patients with high EZH2 levels (Varambally et al. , 2002; Kleer et al., 2003). Recently, inactivation of mutations in UTX (a ubiquitously transcribed tetratricopeptide repeat X), an H3K27 demethylase that functions inversely against EZH2, has been shown to be associated with multiple solid and blood tumor types. Identified in (including kidney, glioblastoma, esophagus, breast, colon, non-small cell lung, small cell lung, bladder, multiple myeloma, and chronic myeloid leukemia tumors) and low UTX levels in breast cancer Correlates with poor survival in, suggesting that loss of UTX function leads to increased H3K27me3 and suppression of target genes (Wang et al., 2010). Taken together, these data suggest that increased H3K27me3 levels contribute to cancer pathogenicity in many tumor types, and that inhibition of EZH2 activity may provide therapeutic utility.

  Many studies have shown that EZH2 direct knockdown by siRNA or shRNA or indirect loss of EZH2 by treatment with the SAH hydrolase inhibitor 3-deazaneplanocin A (DZNep) has been shown in cancer cells in vitro. It has been reported to reduce strain growth and invasion, and in vivo tumor growth (Gonzalez et al., 2008, GBM 2009). Although the exact mechanism by which abnormal EZH2 activity results in cancer progression is not known, many EZH2 target genes are tumor suppressors, suggesting that loss of tumor suppressor function is a key mechanism (References (refs)). In addition, EZH2 overexpression in immortalized or primary epithelial cells promotes fixation independent of growth and invasion and requires EZH2 catalytic activity (Kleer et al., 2003; Cao et al., 2008) .

  Thus, there is strong evidence to suggest that inhibition of EZH2 activity reduces cell proliferation and invasion. Therefore, compounds that inhibit EZH2 activity will be useful for cancer therapy. The azaindazole of the present invention provides such a treatment.

  In a first example, the present invention provides a compound of formula (I) or a salt thereof:

｛式中、
ＸおよびＺが、水素、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_２‐Ｃ_８）アルケニル、（Ｃ_２‐Ｃ_８）アルキニル、非置換または置換された（Ｃ_３‐Ｃ_８）シクロアルキル、非置換または置換された（Ｃ_３‐Ｃ_８）シクロアルキル‐（Ｃ_１‐Ｃ_８）アルキルまたは‐（Ｃ_２‐Ｃ_８）アルケニル、非置換または置換された（Ｃ_５‐Ｃ_８）シクロアルケニル、非置換または置換された（Ｃ_５‐Ｃ_８）シクロアルケニル‐（Ｃ_１‐Ｃ_８）アルキルまたは‐（Ｃ_２‐Ｃ_８）アルケニル、（Ｃ_６‐Ｃ_１０）ビシクロアルキル、非置換または置換されたヘテロシクロアルキル、非置換または置換されたヘテロシクロアルキル‐（Ｃ_１‐Ｃ_８）アルキルまたは‐（Ｃ_２‐Ｃ_８）アルケニル、非置換または置換されたアリール、非置換または置換されたアリール‐（Ｃ_１‐Ｃ_８）アルキルまたは‐（Ｃ_２‐Ｃ_８）アルケニル、非置換または置換されたヘテロアリール、非置換または置換されたヘテロアリール‐（Ｃ_１‐Ｃ_８）アルキルまたは‐（Ｃ_２‐Ｃ_８）アルケニル、ハロ、シアノ、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＣＯＮＲ^ａＮＲ^ａＲ^ｂ、‐ＳＲ^ａ、‐ＳＯＲ^ａ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、ニトロ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＯＲ^ａ、‐ＯＣ（Ｏ）Ｒ^ａ、および‐ＯＣ（Ｏ）ＮＲ^ａＲ^ｂからなる群から独立して選択され；
Ｙが、Ｈまたはハロであり；
Ｒ^１が、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_２‐Ｃ_８）アルケニル、（Ｃ_２‐Ｃ_８）アルキニル、非置換または置換された（Ｃ_３‐Ｃ_８）シクロアルキル、非置換または置換された（Ｃ_３‐Ｃ_８）シクロアルキル‐（Ｃ_１‐Ｃ_８）アルキルまたは‐（Ｃ_２‐Ｃ_８）アルケニル、非置換または置換された（Ｃ_５‐Ｃ_８）シクロアルケニル、非置換または置換された（Ｃ_５‐Ｃ_８）シクロアルケニル‐（Ｃ_１‐Ｃ_８）アルキルまたは‐（Ｃ_２‐Ｃ_８）アルケニル、非置換または置換された（Ｃ_６‐Ｃ_１０）ビシクロアルキル、非置換または置換されたヘテロシクロアルキルまたは‐（Ｃ_２‐Ｃ_８）アルケニル、非置換または置換されたヘテロシクロアルキル‐（Ｃ_１‐Ｃ_８）アルキル、非置換または置換されたアリール、非置換または置換されたアリール‐（Ｃ_１‐Ｃ_８）アルキルまたは‐（Ｃ_２‐Ｃ_８）アルケニル、非置換または置換されたヘテロアリール、非置換または置換されたヘテロアリール‐（Ｃ_１‐Ｃ_８）アルキルまたは‐（Ｃ_２‐Ｃ_８）アルケニル、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＣＯＮＲ^ａＮＲ^ａＲ^ｂであり；
Ｒ^３が、水素、（Ｃ_１‐Ｃ_８）アルキル、シアノ、トリフルオロメチル、‐ＮＲ^ａＲ^ｂ、またはハロであり；
Ｒ^６が、水素、ハロ、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_２‐Ｃ_８）アルケニル、（Ｃ_２‐Ｃ_８）アルキニル、非置換または置換された（Ｃ_３‐Ｃ_８）シクロアルキル、非置換または置換された（Ｃ_３‐Ｃ_８）シクロアルキル‐（Ｃ_１‐Ｃ_８）アルキル、非置換または置換された（Ｃ_５‐Ｃ_８）シクロアルケニル、非置換または置換された（Ｃ_５‐Ｃ_８）シクロアルケニル‐（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_６‐Ｃ_１０）ビシクロアルキル、非置換または置換されたヘテロシクロアルキル、非置換または置換されたヘテロシクロアルキル‐（Ｃ_１‐Ｃ_８）アルキル、非置換または置換されたアリール、非置換または置換されたアリール‐（Ｃ_１‐Ｃ_８）アルキル、非置換または置換されたヘテロアリール、非置換または置換されたヘテロアリール‐（Ｃ_１‐Ｃ_８）アルキル、シアノ、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＣＯＮＲ^ａＮＲ^ａＲ^ｂ、‐ＳＲ^ａ、‐ＳＯＲ^ａ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、ニトロ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＯＲ^ａ、‐ＯＣ（Ｏ）Ｒ^ａ、‐ＯＣ（Ｏ）ＮＲ^ａＲ^ｂからなる群から選択され；
ここで、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_２‐Ｃ_８）アルケニル、（Ｃ_２‐Ｃ_８）アルキニル、シクロアルキル、シクロアルケニル、ビシクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリール基が、ハロ、（Ｃ_１‐Ｃ_６）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、（Ｃ_５‐Ｃ_８）シクロアルケニル、（Ｃ_１‐Ｃ_６）ハロアルキル、シアノ、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＳＲ^ａ、‐ＳＯＲ^ａ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、ニトロ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＯＲ^ａ、‐ＯＣ（Ｏ）Ｒ^ａ、‐ＯＣ（Ｏ）ＮＲ^ａＲ^ｂ、ヘテロシクロアルキル、アリール、ヘテロアリール、アリール（Ｃ_１‐Ｃ_４）アルキル、およびヘテロアリール（Ｃ_１‐Ｃ_４）アルキルからなる群から独立して選択される１、２または３つの基によって置換されていてもよく；
ここで、前記アリール、ヘテロアリール、アリール（Ｃ_１‐Ｃ_４）アルキル、またはヘテロアリール（Ｃ_１‐Ｃ_４）アルキルのアリールまたはヘテロアリール部分が、 ハロ、（Ｃ_１‐Ｃ_６）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、（Ｃ_５‐Ｃ_８）シクロアルケニル、（Ｃ_１‐Ｃ_６）ハロアルキル、シアノ、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＳＲ^ａ、‐ＳＯＲ^ａ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、ニトロ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＯＲ^ａ、‐ＯＣ（Ｏ）Ｒ^ａ、および‐ＯＣ（Ｏ）ＮＲ^ａＲ^ｂからなる群から独立して選択される１、２または３つの基によって置換されていてもよく；
Ｒ^ａおよびＲ^ｂが、それぞれ独立して、水素、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_２‐Ｃ_８）アルケニル、（Ｃ_２‐Ｃ_８）アルキニル、（Ｃ_３‐Ｃ_８）シクロアルキル、（Ｃ_５‐Ｃ_８）シクロアルケニル、（Ｃ_６‐Ｃ_１０）ビシクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリールであり、ここで、前記（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_２‐Ｃ_８）アルケニル、（Ｃ_２‐Ｃ_８）アルキニル、シクロアルキル、シクロアルケニル、ビシクロアルキル、ヘテロシクロアルキル、アリールまたはヘテロアリール基が、ハロ、ヒドロキシル、（Ｃ_１‐Ｃ_４）アルコキシ、アミノ、（Ｃ_１‐Ｃ_４）アルキルアミノ、（（Ｃ_１‐Ｃ_４）アルキル）（（Ｃ_１‐Ｃ_４）アルキル）アミノ、‐ＣＯ_２Ｈ、‐ＣＯ_２（Ｃ_１‐Ｃ_４）アルキル、‐ＣＯＮＨ_２、‐ＣＯＮＨ（Ｃ_１‐Ｃ_４）アルキル、‐ＣＯＮ（（Ｃ_１‐Ｃ_４）アルキル）（（Ｃ_１‐Ｃ_４）アルキル）、‐ＳＯ_２（Ｃ_１‐Ｃ_４）アルキル、‐ＳＯ_２ＮＨ_２、‐ＳＯ_２ＮＨ（Ｃ_１‐Ｃ_４）アルキル、または‐ＳＯ_２Ｎ（（Ｃ_１‐Ｃ_４）アルキル）（（Ｃ_１‐Ｃ_４）アルキル）から独立して選択される１、２または３つの基によって置換されていてもよく；
またはＲ^ａおよびＲ^ｂが、それらが結合する窒素とともに、酸素、窒素、およびイオウから選択されるさらなるヘテロ原子を含んでいてもよい５〜８員の飽和または不飽和環を表わし、ここで、前記環が、（Ｃ_１‐Ｃ_４）アルキル、（Ｃ_１‐Ｃ_４）ハロアルキル、アミノ、（Ｃ_１‐Ｃ_４）アルキルアミノ、（（Ｃ_１‐Ｃ_４）アルキル）（（Ｃ_１‐Ｃ_４）アルキル）アミノ、ヒドロキシル、オキソ、（Ｃ_１‐Ｃ_４）アルコキシ、および（Ｃ_１‐Ｃ_４）アルコキシ（Ｃ_１‐Ｃ_４）アルキルから独立して選択される１、２または３つの基によって置換されていてもよく、ここで、前記環が、（Ｃ_３‐Ｃ_８）シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリール環に縮合していてもよく；
またはＲ^ａおよびＲ^ｂが、それらが結合する窒素とともに、（Ｃ_３‐Ｃ_８）シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリール環に縮合していてもよい６〜１０員の架橋二環式環系を表わす｝に関する。

{Where
X and Z are hydrogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, unsubstituted or substituted (C ₃ -C ₈ ) cycloalkyl, unsubstituted or substituted _(C 3 -C ₈₎ cycloalkyl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈₎ alkenyl, unsubstituted or substituted _(C 5 -C ₈₎ cycloalkenyl , Unsubstituted or substituted (C ₅ -C ₈ ) cycloalkenyl- (C ₁ -C ₈ ) alkyl or-(C ₂ -C ₈ ) alkenyl, (C ₆ -C ₁₀ ) bicycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heterocycloalkyl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈₎ alkenyl, unsubstituted or substituted aryl Unsubstituted or substituted aryl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈₎ alkenyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈₎ alkenyl, halo, ^{_{cyano, -COR a, -CO 2 R a}} , -CONR a R b, -CONR a NR a R b, -SR a, -SOR a, ^{_{-SO 2 R a, -SO 2 NR}} a R b, ^{nitro, -NR a R b, -NR a} C (O) R b, -NR a C (O) NR a R b, -NR a C (O ) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —NR ^a NR ^a R ^b , —NR ^a NR ^a C (O) R ^b , —NR ^a NR ^a C (O ) NR ^a R ^b , -NR ^a NR ^a C Independently selected from the group consisting of (O) OR ^a , —OR ^a , —OC (O) R ^a , and —OC (O) NR ^a R ^b ;
Y is H or halo;
R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, unsubstituted or substituted (C ₃ -C ₈ ) cycloalkyl, unsubstituted or Substituted (C ₃ -C ₈ ) cycloalkyl- (C ₁ -C ₈ ) alkyl or-(C ₂ -C ₈ ) alkenyl, unsubstituted or substituted (C ₅ -C ₈ ) cycloalkenyl, unsubstituted Or substituted (C ₅ -C ₈ ) cycloalkenyl- (C ₁ -C ₈ ) alkyl or-(C ₂ -C ₈ ) alkenyl, unsubstituted or substituted (C ₆ -C ₁₀ ) bicycloalkyl, non- unsubstituted or substituted heterocycloalkyl or - (C 2 _{-C 8)} alkenyl, unsubstituted or substituted heterocycloalkyl - (C 1 _{-C 8)} alkyl, unsubstituted or substituted Aryl, unsubstituted or substituted aryl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈₎ alkenyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaryl - _{(C 1} -C ₈₎ alkyl or - _(C 2 -C _{8) ^{alkenyl, -COR a, -CO 2 R a}} , -CONR a R b, be a -CONR ^a NR ^a R ^b;
R ³ is hydrogen, (C ₁ -C ₈ ) alkyl, cyano, trifluoromethyl, —NR ^a R ^b , or halo;
R ⁶ is hydrogen, halo, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, unsubstituted or substituted (C ₃ -C ₈ ) cycloalkyl , unsubstituted or substituted _(C 3 -C ₈₎ cycloalkyl - _(C 1 -C ₈₎ alkyl, unsubstituted or substituted _(C 5 -C ₈₎ cycloalkenyl, unsubstituted or substituted (C _5- C ₈ ) cycloalkenyl- (C ₁ -C ₈ ) alkyl, (C ₆ -C ₁₀ ) bicycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted heterocycloalkyl- (C ₁ -C ₈₎ alkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl - (C 1 _{-C 8)} alkyl, unsubstituted or substituted heteroaryl, unsubstituted Or substituted heteroaryl- (C ₁ -C ₈ ) alkyl, cyano, —COR ^a , —CO ₂ R ^a , —CONR ^a R ^b , —CONR ^a NR ^a R ^b , —SR ^a , —SOR ^a , ^{_{-SO 2 R a, -SO 2 NR}} a R b, ^{nitro, -NR a R b, -NR a} C (O) R b, -NR a C (O) NR a R b, -NR a C (O ) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —NR ^a NR ^a R ^b , —NR ^a NR ^a C (O) R ^b , —NR ^a NR ^a C (O ) NR ^a R ^b , —NR ^a NR ^a C (O) OR ^a , —OR ^a , —OC (O) R ^a , —OC (O) NR ^a R ^b ;
Where (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are , Halo, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₅ -C ₈ ) cycloalkenyl, (C ₁ -C ₆ ) haloalkyl, cyano, —COR ^a , —CO ₂ R ^a , —CONR ^a R ^b , —SR ^a , —SOR ^a , —SO ₂ R ^a , —SO ₂ NR ^a R ^b , nitro, —NR ^a R ^b , —NR ^a C (O) R ^b , — NR ^a C (O) NR ^a R ^b , —NR ^a C (O) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —OR ^a , —OC (O) R ^a , -OC (O) NR 1, 2 or 3 independently selected from the group consisting of ^a R ^b , heterocycloalkyl, aryl, heteroaryl, aryl (C ₁ -C ₄ ) alkyl, and heteroaryl (C ₁ -C ₄ ) alkyl Optionally substituted by a group;
Wherein the aryl, heteroaryl, aryl (C ₁ -C ₄ ) alkyl, or heteroaryl (C ₁ -C ₄ ) alkyl aryl or heteroaryl moiety is halo, (C ₁ -C ₆ ) alkyl, ( C ₃ -C _{8) cycloalkyl, (C} 5 -C _{8) cycloalkenyl, (C} 1 -C ₆₎ haloalkyl, ^{_{cyano, -COR a, -CO 2 R a}} , -CONR a R b, -SR a, -SOR ^a , -SO ₂ R ^a , -SO ₂ NR ^a R ^b , nitro, -NR ^a R ^b , -NR ^a C (O) R ^b , -NR ^a C (O) NR ^a R ^b , -NR ^a C (O) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —OR ^a , —OC (O) R ^a , and —OC (O) NR ^a R ^b Selected independently of group Optionally substituted by 1, 2 or 3 groups;
R ^a and R ^b are each independently hydrogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl. , (C ₅ -C ₈ ) cycloalkenyl, (C ₆ -C ₁₀ ) bicycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein (C ₁ -C ₈ ) alkyl, (C ₂ -C _{8) alkenyl, (C} 2 -C ₈₎ alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl or heteroaryl group, halo, _{hydroxy, (C} 1 -C ₄₎ alkoxy, amino, (C _1- C ₄ ) alkylamino, ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) alkyl) amino, —CO ₂ H, —CO ₂ (C ₁ -C ₄ ) alkyl, —CONH ₂ , —CONH (C ₁ -C ₄ ) alkyl, —CON ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) alkyl), —SO ₂ (C ₁ -C ₄ ) alkyl, —SO ₂ NH ₂ , —SO ₂ NH (C ₁ -C ₄ ) alkyl, or —SO ₂ N ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) Optionally substituted by 1, 2 or 3 groups independently selected from alkyl);
Or R ^a and R ^b together with the nitrogen to which they are attached represent a 5- to 8-membered saturated or unsaturated ring that may contain additional heteroatoms selected from oxygen, nitrogen, and sulfur, wherein The ring is (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl, amino, (C ₁ -C ₄ ) alkylamino, ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) 1, 2 or 3 groups independently selected from alkyl) amino, hydroxyl, oxo, (C ₁ -C ₄ ) alkoxy, and (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkyl Wherein the ring may be fused to a (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
Or R ^a and R ^b together with the nitrogen to which they are attached, a 6-10 membered bridged bicycle optionally fused to a (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring Represents a formula ring system}.

  In a further iteration of the invention, it relates to a method of treating cancer.

  Another aspect of the present invention is a medicament comprising a compound of formula (I) and a pharmaceutically acceptable excipient.

  In a fourth aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inhibiting EZH2, such as inducing apoptosis in cancer cells The use of possible salts or solvates is provided.

  In a fifth aspect, there is provided a method of co-administering a compound of formula (I) invented in the present invention with another active ingredient.

  For the avoidance of doubt, unless otherwise indicated, the term “substituted” means substituted by one or more defined groups. If the group can be selected from many alternative groups, the selected group can be the same or different.

  The term “independently” means that when two or more substituents are selected from a number of possible groups, the substituents may be the same or different.

  “Effective amount” means the amount of a drug or pharmaceutical agent that would elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for example, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” refers to a treatment, cure, prevention, or amelioration, or disease or disorder with improved disease, disorder, or side effects compared to a corresponding subject that has not received such an amount. It means an amount that causes a decrease in the speed of progression. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein, the term “alkyl” means a straight or branched chain hydrocarbon group having the specified number of carbon atoms, eg, as used herein, “C The term “ _1- C ₈ alkyl” means an alkyl group having at least one and at most 8 carbon atoms each. Such branched or straight chain alkyl groups useful in the present invention include, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl. , N-heptyl, and n-octyl as well as branched analogs of the last five linear alkanes.

As used herein, the term “alkoxy” is defined above as alkyl, including —OCH ₃ , —OCH ₂ CH _3, —OC (CH ₃ ) _{3, and the} like —O (C ₁ -C ₈ alkyl. ).

As used herein, the term “alkylthio” refers to —S (C ₁ -C ₈ alkyl) as defined above for alkyl, including —SCH ₃ , —SCH ₂ CH _{3 and the} like.

The term “acyloxy” means —OC (O) C ₁ -C ₈ alkyl or the like in the above definition of alkyl.

“Acylamino” means N (H) C (O) C ₁ -C ₈ alkyl, etc., as defined above for alkyl.

  “Aryloxy” means —O (aryl), —O (substituted aryl), —O (heteroaryl) or —O (substituted heteroaryl).

  “Arylamino” means —NH (aryl), —NH (substituted aryl), —NH (heteroaryl), —NH (substituted heteroaryl) or the like.

  When the term “alkenyl” (or “alkenylene”) is used, it is a straight or branched chain containing the specified number of carbon atoms and at least one and up to five carbon-carbon double bonds. Refers to a hydrocarbon chain. Examples include ethenyl (or ethenylene) and propenyl (or propenylene).

  When the term “alkynyl” (or “alkynylene”) is used, it is a straight or branched carbon chain containing the specified number of carbon atoms and at least one and up to five carbon-carbon triple bonds. Refers to the hydrogen chain. Examples include ethynyl (or ethynylene) and propynyl (or propynylene).

  “Haloalkyl” refers to an alkyl group substituted with one or more halo substituents, preferably 1 to 6 substituents. Haloalkyl includes trifluoromethyl.

When “cycloalkyl” is used, it refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. Thus, for example, the term “C ₃ -C ₈ cycloalkyl” refers to a non-aromatic hydrocarbon ring having from 3 to 8 carbon atoms. Exemplary “C ₃ -C ₈ cycloalkyl” groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term “C ₅ -C ₈ cycloalkenyl” refers to a non-aromatic monocyclic carbocyclic ring having the specified number of carbon atoms and up to 3 carbon-carbon double bonds. “Cycloalkenyl” includes, for example, cyclopentenyl and cyclohexenyl.

When “C ₃ -C ₈ heterocycloalkyl” is used, it contains a specified number of ring atoms that are saturated or have one or more degrees of unsaturation and is independently selected from O, S, and N Means a non-aromatic heterocycle containing one or more heteroatom substitutions. Such rings may be fused to one or more other “heterocycles” or cycloalkyl rings. Examples are given herein below.

  “Aryl” refers to a non-fused or fused group of optionally substituted mono- and polycyclic carbocycles having from 6 to 14 carbon atoms and having at least one aromatic ring following the Hückel rule. As further described below, examples of aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, and the like.

  “Heteroaryl” contains at least one heteroatom in which at least one ring follows the Hückel rule and has the specified number of ring atoms, the ring being independently selected from N, O, and S , Means an optionally substituted aromatic monocyclic or polycyclic fused carbocyclic ring system. Examples of “heteroaryl” groups are given herein below.

  The term “optionally” means that the previously described event may or may not occur and includes both events that occur and events that do not occur.

  As used herein, the term “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the subject compound and has minimal undesirable toxicological effects. These pharmaceutically acceptable salts are either prepared in situ during the final isolation and purification of the compound or individually purified compounds in the form of the free acid or free base. Each may be prepared by reacting with a suitable base or acid.

  Although the compounds encompassed by the general structure of formula (I) as defined herein are believed to be useful in inducing apoptosis in cancer cells, some of these compounds are more active than others. There is. In connection therewith, the following subgroups describe in detail certain compounds that may have higher potency compared to others, or other properties that suggest a better choice for use in therapy. To do. These subgroups are shown below.

（１）では、
Ａが、Ｏ、ＮＨ、もしくはＳであり；Ｂが、ＣＨもしくはＮであり、およびＣが、水素もしくはＣ_１‐Ｃ_８アルキルであり；または

（２）では、
Ｄが、水素もしくはＣ_１‐Ｃ_８アルキルによって置換されていてもよいＮもしくはＣ；または

（３）では、
Ｅが、ＮＨもしくはＣＨ_２であり；Ｆが、ＯもしくはＣＯであり；およびＧが、ＮＨもしくはＣＨ_２であり；または

（４）では、
Ｊが、Ｏ、ＳもしくはＣＯであり；または

（５）では、
Ｑが、ＣＨもしくはＮであり；
Ｍが、ＣＨもしくはＮであり；および
Ｌ／（５）が、水素、ハロ、アミノ、シアノ、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＣＯＮＲ^ａＮＲ^ａＲ^ｂ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＯＲ^ａであり、 そこにおいて、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル基が、（Ｃ_１‐Ｃ_６）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、（Ｃ_５‐Ｃ_８）シクロアルケニル、（Ｃ_１‐Ｃ_６）ハロアルキル、シアノ、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＳＲ^ａ、‐ＳＯＲ^ａ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、ニトロ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＯＲ^ａ、‐ＯＣ（Ｏ）Ｒ^ａ、‐ＯＣ（Ｏ）ＮＲ^ａＲ^ｂから独立して選択される１、２または３つの基によって置換されていてもよく、ここで、Ｒ^ａおよびＲ^ｂが、上記のように定義され；または

６では、
Ｌ／（６）が、ＮＨもしくはＣＨ_２であり；または

７では、
Ｍ／（７）が、水素、ハロ、アミノ、シアノ、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、ヘテロシクロアルキル、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＣＯＮＲ^ａＮＲ^ａＲ^ｂ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＯＲ^ａであり、
そこにおいて、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、ヘテロシクロアルキル基が、（Ｃ_１‐Ｃ_６）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、（Ｃ_５‐Ｃ_８）シクロアルケニル、（Ｃ_１‐Ｃ_６）ハロアルキル、シアノ、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＳＲ^ａ、‐ＳＯＲ^ａ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、ニトロ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＯＲ^ａ、‐ＯＣ（Ｏ）Ｒ^ａ、‐ＯＣ（Ｏ）ＮＲ^ａＲ^ｂから独立して選択される１、２または３つの基によって置換されていてもよく；ここで、Ｒ^ａおよびＲ^ｂが、上記のように定義され；または

（８）では、
Ｐが、ＣＨ_２、ＮＨ、Ｏ、もしくはＳであり；Ｑ／（８）が、ＣＨもしくはＮ；およびｎが、０〜２であり；または

（９）では、
Ｓ／（９）およびＴ（９）がＣ、もしくはＳ／（９）がＣおよびＴ（９）がＮ、もしくはＳ／（９）がＮおよびＴ／（９）がＣであり；
Ｒが、水素、アミノ、メチル、トリフルオロメチル、ハロであり；
Ｕが、水素、ハロ、アミノ、シアノ、ニトロ、トリフルオロメチル、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＯＲ^ａ、４‐（１Ｈ‐ピラゾール‐４‐イル）であり、 そこにおいて、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル基が、（Ｃ_１‐Ｃ_６）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、（Ｃ_５‐Ｃ_８）シクロアルケニル、（Ｃ_１‐Ｃ_６）ハロアルキル、シアノ、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＳＲ^ａ、‐ＳＯＲ^ａ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、ニトロ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＯＲ^ａ、‐ＯＣ（Ｏ）Ｒ^ａ、‐ＯＣ（Ｏ）ＮＲ^ａＲ^ｂから独立して選択される１、２または３つの基によって置換されていてもよく、ここで、Ｒ^ａおよびＲ^ｂが、上記のように定義される。 Subgroup A
X and Z are selected from the group consisting of (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR ^a R ^b , and —OR ^a ;
Y is H or F;
R ¹ is selected from the group consisting of (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
R ³ is selected from the group consisting of hydrogen, (C ₁ -C ₈ ) alkyl, cyano, trifluoromethyl, —NR ^a R ^b , and halo;
R ⁶ is hydrogen, halo, cyano, trifluoromethyl, amino, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl; aryl, heteroaryl, acylamino, (C ₂ -C ₈ ) Alkynyl, arylalkynyl, heteroarylalkynyl; selected from the group consisting of —SO ₂ R ^a ; —SO ₂ NR ^a R ^b , and —NR ^a SO ₂ R ^b ;
Here, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ -C ₈ ) alkynyl, arylalkynyl, heteroarylalkynyl groups are halo, (C ₁ -C ₆ ) alkyl , (C ₃ -C ₈ ) cycloalkyl, (C ₅ -C ₈ ) cycloalkenyl, (C ₁ -C ₆ ) haloalkyl, cyano, -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -SR ^a , —SOR ^a , —SO ₂ R ^a , —SO ₂ NR ^a R ^b , nitro, —NR ^a R ^b , —NR ^a C (O) R ^b , —NR ^a C (O) NR ^a R ^b , _{^{-NR a C (O) OR a}} , -NR a SO 2 R b, -NR a SO 2 NR a R b, -OR a, -OC (O) R a, -OC (O) NR a R b, Heterocycloalkyl, aryl, heteroary , Aryl _(C 1 -C ₄₎ alkyl, and heteroaryl _(C 1 -C ₄₎ may be substituted by one, two or three groups independently selected from alkyl;
R ^a and R ^b are each independently hydrogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl. , (C ₅ -C ₈ ) cycloalkenyl, (C ₆ -C ₁₀ ) bicycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein (C ₁ -C ₈ ) alkyl, (C ₂ -C _{8) alkenyl, (C} 2 -C ₈₎ alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl or heteroaryl group, halo, _{hydroxy, (C} 1 -C ₄₎ alkoxy, amino, (C _1- C ₄ ) alkylamino, ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) alkyl) amino, —CO ₂ H, —CO ₂ (C ₁ -C ₄ ) alkyl, —CONH ₂ , —CONH (C ₁ -C ₄ ) alkyl, —CON ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) alkyl), —SO ₂ (C ₁ -C ₄ ) alkyl, —SO ₂ NH ₂ , —SO ₂ NH (C ₁ -C ₄ ) alkyl, and —SO ₂ N ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) Optionally substituted by 1, 2 or 3 groups independently selected from alkyl);
Or R ^a and R ^b together with the nitrogen to which they are attached represent a 5- to 8-membered saturated or unsaturated ring that may contain additional heteroatoms selected from oxygen, nitrogen, and sulfur, wherein The ring is (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl, amino, (C ₁ -C ₄ ) alkylamino, ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) 1, 2 or 3 groups independently selected from alkyl) amino, hydroxyl, oxo, (C ₁ -C ₄ ) alkoxy, and (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkyl Wherein the ring may be fused to a (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
Or R ^a and R ^b together with the nitrogen to which they are attached, a 6-10 membered bridged bicycle optionally fused to a (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring Represents a formula ring system. The aryl or heteroaryl group in this particular subgroup A is furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, It is independently selected from the group consisting of phenyl, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, quinoline, cinnoline, quinazoline, quinoxaline, and naphthyridine, or another aryl or heteroaryl group:

(1)
A is O, NH, or S; B is CH or N, and C is hydrogen or C ₁ -C ₈ alkyl; or

(2)
D is hydrogen or N or C optionally substituted by C ₁ -C ₈ alkyl; or

(3)
E is NH or CH ₂ ; F is O or CO; and G is NH or CH ₂ ; or

(4)
J is O, S or CO; or

(5)
Q is CH or N;
M is CH or N; and L / (5) is hydrogen, halo, amino, cyano, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, —COR ^a , —CO ₂ R ^a , —CONR ^a R ^b , —CONR ^a NR ^a R ^b , —SO ₂ R ^a , —SO ₂ NR ^a R ^b , —NR ^a R ^b , —NR ^a C (O) R ^b , —NR ^{_{a SO 2 R b, -NR a}} SO 2 NR a R b, -NR a NR a R b, -NR a NR a C (O) R b, -NR a NR a C (O) NR a R b, -OR ^a where (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl group is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, ( C ₅ -C _{8) cycloalkenyl, (C} 1 -C ₆₎ haloalkyl, ^{_{Ano, -COR a, -CO 2 R a}} , -CONR a R b, -SR a, -SOR a, -SO 2 R a, -SO 2 NR a R b, ^nitro, -NR ^a R ^b, -NR ^{a C (O) R b,} -NR a C (O) NR a R b, -NR a C (O) OR a, -NR a SO 2 R b, -NR a SO 2 NR a R b, -OR ^a , —OC (O) R ^a , —OC (O) NR ^a R ^b may be substituted by one, two or three groups independently selected, wherein R ^a and R ^b are Defined as above; or

In 6,
L / (6) is NH or CH ₂ ; or

7
M / (7) is hydrogen, halo, amino, cyano, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, —COR ^a , —CO ₂ R ^a , —CONR ^{a R b, -CONR a NR a} R b, -SO 2 R a, -SO 2 NR a R b, -NR a R b, -NR a C (O) R b, -NR a SO 2 R b, ^{_{-NR a SO 2 NR a R b}} , -NR a NR a R b, -NR a NR a C (O) R b, -NR a NR a C (O) NR a R b, is -OR ^a,
Wherein (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl groups are (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₅ -C _{8) cycloalkenyl, (C} 1 -C ₆₎ haloalkyl, ^{_{cyano, -COR a, -CO 2 R a}} , -CONR a R b, -SR a, -SOR a, -SO 2 R a, -SO ₂ NR ^a R ^b , nitro, —NR ^a R ^b , —NR ^a C (O) R ^b , —NR ^a C (O) NR ^a R ^b , —NR ^a C (O) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —OR ^a , —OC (O) R ^a , —OC (O) NR ^a R ^b It may be substituted; wherein, ^{R a} and ^{R b} are, Serial is defined as; or

(8)
P _is CH 2, NH, O, or be S; Q / (8) is CH or N; and n, be 0-2; or

(9)
S / (9) and T (9) are C, or S / (9) is C and T (9) is N, or S / (9) is N and T / (9) is C;
R is hydrogen, amino, methyl, trifluoromethyl, halo;
U is hydrogen, halo, amino, cyano, nitro, trifluoromethyl, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, —COR ^a , —CO ₂ R ^a , —CONR ^a R ^{_{b, -SO 2 R a, -SO}} 2 NR a R b, -NR a R b, -NR a C (O) R b, -NR a SO 2 R b, -NR a SO 2 NR a R b, -NR ^a NR ^a R ^b , -NR ^a NR ^a C (O) R ^b , -OR ^a , 4- (1H-pyrazol-4-yl), wherein (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl group is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₅ -C ₈ ) cycloalkenyl, (C ₁ -C ₆ ) haloalkyl, ^{_{cyano, -COR a, -CO 2 R a}} , -CO ^{R a R b, -SR a,} -SOR a, -SO 2 R a, -SO 2 NR a R b, ^{nitro, -NR a R b, -NR a} C (O) R b, -NR a C ( O) NR ^a R ^b , —NR ^a C (O) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —OR ^a , —OC (O) R ^a , —OC ( O) optionally substituted by 1, 2 or 3 groups independently selected from NR ^a R ^b , where R ^a and R ^b are defined as above.

（１）では、
Ａが、Ｏ、ＮＨ、もしくはＳであり；Ｂが、ＣＨもしくはＮであり、およびＣが、水素もしくはＣ_１‐Ｃ_８アルキルであり；または

（２）では、
Ｄが、水素もしくはＣ_１‐Ｃ_８アルキルによって置換されていてもよいＮもしくはＣであり；または

（３）では、
Ｅが、ＮＨもしくはＣＨ_２であり；Ｆが、ＯもしくはＣＯであり；およびＧが、ＮＨもしくはＣＨ_２であり；または

（４）では、
Ｊが、Ｏ、ＳもしくはＣＯであり；または

（５）では、
Ｑが、ＣＨもしくはＮであり；
Ｍが、ＣＨもしくはＮであり；および
Ｌ／（５）が、水素、ハロ、アミノ、シアノ、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＣＯＮＲ^ａＮＲ^ａＲ^ｂ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＯＲ^ａであり、 ここで、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル基が、（Ｃ_１‐Ｃ_６）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、（Ｃ_５‐Ｃ_８）シクロアルケニル、（Ｃ_１‐Ｃ_６）ハロアルキル、シアノ、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＳＲ^ａ、‐ＳＯＲ^ａ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、ニトロ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＯＲ^ａ、‐ＯＣ（Ｏ）Ｒ^ａ、‐ＯＣ（Ｏ）ＮＲ^ａＲ^ｂから独立して選択される１、２または３つの基によって置換されていてもよく、ここで、Ｒ^ａおよびＲ^ｂが、上記のように定義され；または

（６）では、
Ｌ／（６）が、ＮＨもしくはＣＨ_２であり；または

（７）では、
Ｍ／（７）が、水素、ハロ、アミノ、シアノ、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、ヘテロシクロアルキル、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＣＯＮＲ^ａＮＲ^ａＲ^ｂ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＯＲ^ａであり、
ここで、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、ヘテロシクロアルキル基が、（Ｃ_１‐Ｃ_６）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、（Ｃ_５‐Ｃ_８）シクロアルケニル、（Ｃ_１‐Ｃ_６）ハロアルキル、シアノ、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＳＲ^ａ、‐ＳＯＲ^ａ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、ニトロ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＯＲ^ａ、‐ＯＣ（Ｏ）Ｒ^ａ、‐ＯＣ（Ｏ）ＮＲ^ａＲ^ｂから独立して選択される１、２または３つの基によって置換されていてもよく；ここで、Ｒ^ａおよびＲ^ｂが、上記のように定義され；または

（８）では、
Ｐが、ＣＨ_２、ＮＨ、Ｏ、もしくはＳであり；Ｑ／（８）が、ＣＨもしくはＮ；およびｎが、０〜２であり；または

（９）では、
Ｓ／（９）およびＴ（９）がＣであるか、もしくはＳ／（９）がＣおよびＴ（９）がＮであるか、もしくはＳ／（９）がＮおよびＴ／（９）がＣであり；
Ｒが、水素、アミノ、メチル、トリフルオロメチル、ハロであり；
Ｕが、水素、ハロ、アミノ、シアノ、ニトロ、トリフルオロメチル、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＲ^ｂ、‐ＮＲ^ａＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＯＲ^ａ、４‐（１Ｈ‐ピラゾール‐４‐イル）であり、 ここで、（Ｃ_１‐Ｃ_８）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル基が、（Ｃ_１‐Ｃ_６）アルキル、（Ｃ_３‐Ｃ_８）シクロアルキル、（Ｃ_５‐Ｃ_８）シクロアルケニル、（Ｃ_１‐Ｃ_６）ハロアルキル、シアノ、‐ＣＯＲ^ａ、‐ＣＯ_２Ｒ^ａ、‐ＣＯＮＲ^ａＲ^ｂ、‐ＳＲ^ａ、‐ＳＯＲ^ａ、‐ＳＯ_２Ｒ^ａ、‐ＳＯ_２ＮＲ^ａＲ^ｂ、ニトロ、‐ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）Ｒ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＮＲ^ａＲ^ｂ、‐ＮＲ^ａＣ（Ｏ）ＯＲ^ａ、‐ＮＲ^ａＳＯ_２Ｒ^ｂ、‐ＮＲ^ａＳＯ_２ＮＲ^ａＲ^ｂ、‐ＯＲ^ａ、‐ＯＣ（Ｏ）Ｒ^ａ、‐ＯＣ（Ｏ）ＮＲ^ａＲ^ｂから独立して選択される１、２または３つの基によって置換されていてもよく；ここで、Ｒ^ａおよびＲ^ｂが、上記のように定義される。 Subgroup B
Independently from the group consisting of X and Z are (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR ^a R ^b , and —OR ^a Selected;
Y is H;
R ¹ is (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, or heterocycloalkyl;
R ³ is hydrogen, (C ₁ -C ₈ ) alkyl or halo;
R ⁶ is hydrogen, halo, cyano, trifluoromethyl, amino, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl, heteroaryl, acylamino, (C ₂ -C ₈ ) alkynyl , Arylalkynyl, heteroarylalkynyl, —SO ₂ R ^a ; —SO ₂ NR ^a R ^b , or —NR ^a SO ₂ R ^b ;
Here, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ -C ₈ ) alkynyl, arylalkynyl, heteroarylalkynyl groups are halo, (C ₁ -C ₆ ) alkyl , (C ₃ -C ₈ ) cycloalkyl, (C ₅ -C ₈ ) cycloalkenyl, (C ₁ -C ₆ ) haloalkyl, cyano, -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -SR ^a , —SOR ^a , —SO ₂ R ^a , —SO ₂ NR ^a R ^b , nitro, —NR ^a R ^b , —NR ^a C (O) R ^b , —NR ^a C (O) NR ^a R ^b , _{^{-NR a C (O) OR a}} , -NR a SO 2 R b, -NR a SO 2 NR a R b, -OR a, -OC (O) R a, -OC (O) NR a R b, Heterocycloalkyl, aryl, heteroary , Aryl _(C 1 -C ₄₎ alkyl, and heteroaryl _(C 1 -C ₄₎ may be substituted by one, two or three groups independently selected from alkyl;
R ^a and R ^b are each independently hydrogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl. , (C ₅ -C ₈ ) cycloalkenyl, (C ₆ -C ₁₀ ) bicycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein (C ₁ -C ₈ ) alkyl, (C ₂ -C _{8) alkenyl, (C} 2 -C ₈₎ alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl or heteroaryl group, halo, _{hydroxy, (C} 1 -C ₄₎ alkoxy, amino, (C _1- C ₄ ) alkylamino, ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) alkyl) amino, —CO ₂ H, —CO ₂ (C ₁ -C ₄ ) alkyl, —CONH ₂ , —CONH (C ₁ -C ₄ ) alkyl, —CON ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) alkyl), —SO ₂ (C ₁ -C ₄ ) alkyl, —SO ₂ NH ₂ , —SO ₂ NH (C ₁ -C ₄ ) alkyl, and —SO ₂ N ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) Optionally substituted by 1, 2 or 3 groups independently selected from alkyl);
Or R ^a and R ^b together with the nitrogen to which they are attached represent a 5- to 8-membered saturated or unsaturated ring that may contain additional heteroatoms selected from oxygen, nitrogen, and sulfur, wherein The ring is (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl, amino, (C ₁ -C ₄ ) alkylamino, ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) 1, 2 or 3 groups independently selected from alkyl) amino, hydroxyl, oxo, (C ₁ -C ₄ ) alkoxy, and (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkyl Wherein the ring may be fused to a (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
Or R ^a and R ^b together with the nitrogen to which they are attached, a 6-10 membered bridged bicycle optionally fused to a (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring Represents a formula ring system. Aryl and heteroaryl in this definition are furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, phenyl, pyridine, pyridazine , Pyrimidine, pyrazine, triazine, tetrazine, quinoline, cinnoline, quinazoline, quinoxaline, and naphthyridine, or another aryl or heteroaryl group compound:

(1)
A is O, NH, or S; B is CH or N, and C is hydrogen or C ₁ -C ₈ alkyl; or

(2)
D is hydrogen or N or C optionally substituted by C ₁ -C ₈ alkyl; or

(3)
E is NH or CH ₂ ; F is O or CO; and G is NH or CH ₂ ; or

(4)
J is O, S or CO; or

(5)
Q is CH or N;
M is CH or N; and L / (5) is hydrogen, halo, amino, cyano, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, —COR ^a , —CO ₂ R ^a , —CONR ^a R ^b , —CONR ^a NR ^a R ^b , —SO ₂ R ^a , —SO ₂ NR ^a R ^b , —NR ^a R ^b , —NR ^a C (O) R ^b , —NR ^{_{a SO 2 R b, -NR a}} SO 2 NR a R b, -NR a NR a R b, -NR a NR a C (O) R b, -NR a NR a C (O) NR a R b, -OR ^a , wherein (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl group is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, ( C ₅ -C _{8) cycloalkenyl, (C} 1 -C ₆₎ haloalkyl, cyano , -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -SR ^a , -SOR ^a , -SO ₂ R ^a , -SO ₂ NR ^a R ^b , nitro, -NR ^a R ^b , -NR ^a C (O) R ^b , —NR ^a C (O) NR ^a R ^b , —NR ^a C (O) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —OR ^a , —OC (O) R ^a , —OC (O) NR ^a R ^b , optionally substituted by 1, 2 or 3 groups, wherein R ^a and R ^b are Defined as above; or

(6)
L / (6) is NH or CH ₂ ; or

(7)
M / (7) is hydrogen, halo, amino, cyano, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, —COR ^a , —CO ₂ R ^a , —CONR ^{a R b, -CONR a NR a} R b, -SO 2 R a, -SO 2 NR a R b, -NR a R b, -NR a C (O) R b, -NR a SO 2 R b, ^{_{-NR a SO 2 NR a R b}} , -NR a NR a R b, -NR a NR a C (O) R b, -NR a NR a C (O) NR a R b, is -OR ^a,
Here, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, a heterocycloalkyl group is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₅ -C _{8) cycloalkenyl, (C} 1 -C ₆₎ haloalkyl, ^{_{cyano, -COR a, -CO 2 R a}} , -CONR a R b, -SR a, -SOR a, -SO 2 R a, -SO ₂ NR ^a R ^b , nitro, —NR ^a R ^b , —NR ^a C (O) R ^b , —NR ^a C (O) NR ^a R ^b , —NR ^a C (O) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —OR ^a , —OC (O) R ^a , —OC (O) NR ^a R ^b It may be substituted; wherein, R ^a and R ^b are, in the Is urchin defined; or

(8)
P _is CH 2, NH, O, or be S; Q / (8) is CH or N; and n, be 0-2; or

(9)
S / (9) and T (9) are C, or S / (9) is C and T (9) is N, or S / (9) is N and T / (9) is C;
R is hydrogen, amino, methyl, trifluoromethyl, halo;
U is hydrogen, halo, amino, cyano, nitro, trifluoromethyl, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, —COR ^a , —CO ₂ R ^a , —CONR ^a R ^{_{b, -SO 2 R a, -SO}} 2 NR a R b, -NR a R b, -NR a C (O) R b, -NR a SO 2 R b, -NR a SO 2 NR a R b, -NR ^a NR ^a R ^b , -NR ^a NR ^a C (O) R ^b , -OR ^a , 4- (1H-pyrazol-4-yl), wherein (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl group is (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₅ -C ₈ ) cycloalkenyl, (C ₁ -C ₆ ) haloalkyl, Cyano, -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , —SR ^a , —SOR ^a , —SO ₂ R ^a , —SO ₂ NR ^a R ^b , nitro, —NR ^a R ^b , —NR ^a C (O) R ^b , —NR ^a C (O) NR ^a R ^b , —NR ^a C (O) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —OR ^a , —OC (O) R ^a , —OC (O) It may be substituted by 1, 2 or 3 groups independently selected from NR ^a R ^b ; where R ^a and R ^b are defined as above.

Subgroup C
X is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, trifluoromethyl, tetrahydropyran, hydroxymethyl, methoxymethyl, or benzyl;
Y is H;
Z is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or benzyl;
R ¹ is isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, (1-methylethyl) cyclopropyl, 1,1-dioxo-tetrahydrothiophen-3-yl, 1-Me-piperidin-4-yl, tetrahydrofuran- 3-yl, tetrahydropyran-4-yl, N, N-dimethyl-1-propanaminyl, benzyl, or 4-pyridyl;
R ³ is H, methyl, or Br; and R ⁶ is methyl, bis (1,1-dimethylethyl), bis (1-methylethyl), cyclopropyl, propyl, dimethylamino, ethylamino, ( 2-hydroxyethyl) amino, 2-propen-1-ylamino, 1-piperazinyl, 1-piperidinyl, 4-morpholinyl, 4-piperidinylamino, tetrahydro-2H-pyran-4-ylamino, phenylamino, (phenylmethyl) ) Amino, (4-pyridinylmethyl) amino, [2- (2-pyridinylamino) ethyl] amino, 2- (dimethylamino) ethyl] amino, 4-pyridinylamino, 4- (aminocarbonyl) phenyl] amino, 3-hydroxy- 3-methyl-1-butyn-1-yl, 4-pyridinylethynyl, phenyl ester Nyl, 2-furanyl, 3-thienyl; 1H-pyrazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 3-methyl-1H-indazol-5-yl, 1H-1, 2,3-benzotriazol-5-yl, 2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl, 2- Oxo-2,3-dihydro-1H-indol-6-yl, 2,1,3-benzooxadiazol-5-yl, 2-amino-6-quinazolinyl, 2,4-dioxo-1,2,3 , 4-tetrahydro-5-pyrimidinyl, 2-amino-5-pyrimidinyl, 7-oxo-1,5,6,7-tetrahydro-1,8-naphthyridin-3-yl, phenyl, 2-methylphenol 2-nitrophenyl, 2-phenylethyl, 3-aminophenyl, 4-aminophenyl, 4-chlorophenyl, 4-fluorophenyl, 4- (methyloxy) phenyl, 3- (acetylamino) phenyl, 4- ( Acetylamino) phenyl, 4- (aminocarbonyl) phenyl, 4- (1H-pyrazol-4-yl) phenyl, 4- (aminosulfonyl) phenyl, 4- (methylsulfonyl) phenyl, 4-[(dimethylamino) sulfonyl ] Phenyl, 4-[(methylamino) carbonyl] phenyl, 4-[(methylamino) sulfonyl] phenyl, 4-[(methylsulfonyl) amino] phenyl, 3-pyridinyl, 4-pyridinyl, 2- (4-morpholinyl) ) -4-Pyridinyl, 2-amino-4-pyridinyl, 5- (methyloxy) -3-pyridinyl, 5- (methylsulfonyl) -3-pyridinyl, 5-[(cyclopropylsulfonyl) amino] -6- (methyloxy) -3-pyridinyl, 5-[(phenylsulfonyl) amino] -3- Pyridinyl, 6- (4-methyl-1-piperazinyl) -3-pyridinyl, 6- (4-morpholinyl) -3-pyridinyl, 6- (acetylamino) -3-pyridinyl, 6- (dimethylamino) -3- Pyridinyl, 6- (methyloxy) -3-pyridinyl, 6-[(methylamino) carbonyl] -3-pyridinyl, 6-[(methylamino) sulfonyl] -3-pyridinyl, 6-methyl-3-pyridinyl, 4 -Pyridinyloxy.

  Individual compounds can be found in the examples below.

  As used herein, the term “co-administering” and its derivatives, one or more, whether to treat cancer, cancer or side effects of cancer treatment, or some other disease Is meant either co-administration of additional pharmaceutically active compounds or individual sequential administration in any manner. Where administration is not simultaneous, it is preferred that the compounds be administered in close proximity to one another in time. Furthermore, it does not matter whether the compounds are administered in the same dosage form, for example one compound can be administered topically and another compound can be administered orally.

  In certain embodiments, the compound of Formula I may contain an acidic functional group that is acidic enough to form a salt. Exemplary salts include pharmaceutically acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc Pharmaceutically acceptable metal cation carbonates and bicarbonates; aliphatic amines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine, aroma Pharmaceutically acceptable organic primary, secondary, and tertiary amines, including aliphatic amines, aliphatic diamines, and hydroxyalkylamines.

  In certain embodiments, the compounds described by formula (I) may contain a basic functional group, and thus may be treated with a suitable acid to form a pharmaceutically acceptable acid addition salt. it can. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Typical pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate , Phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate , P-aminosalicylate, glycolate, lactate, heptaneate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methyl benzoate, Dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, Rubinate, pamoate, malonate, laurate, glutarate, glutamate, estrate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonic acid Salts, benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate (tosylate) and naphthalene-2-sulfonate.

  All tautomeric forms of the compounds described herein, including mixtures thereof, are intended to be included within the scope of the present invention. In general, the compounds exemplified herein are given names based on the structure of the tautomer of formula (IA). It should be understood that a reference to a named compound of the present invention is intended to encompass all tautomers of the named compound and any mixture of tautomers of the named compound. .

  The compounds of formula (I) are prepared in crystalline or amorphous form, and in the case of crystals can be solvated, for example as hydrates. The present invention includes within its scope stoichiometric solvates (eg hydrates) as well as compounds containing various amounts of solvent (eg water).

  Certain compounds described herein may contain one or more chiral atoms, or may otherwise exist as two enantiomers. The compounds claimed below include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also included within the scope of the invention are the compounds represented by Formula (I), or individual isomers of the compounds claimed below, as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the claimed compounds as mixtures with isomers thereof in which one or more chiral centers are inverted.

  When there are different isomeric forms, they can be separated or resolved separately by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis. sell.

  For use in therapy, compounds of formula (I), and salts, solvates, etc. may be administered as neat preparations, i.e. without the addition of a carrier, It is a more usual practice to present the active ingredient prepared with a diluent. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound and salt of formula (I), a solvate, etc., and one or more pharmaceutically acceptable carriers, diluents or excipients. . The compounds of formula (I) and salts, solvates and the like are as described above. The carrier, diluent or excipient must be acceptable in that it does not affect other ingredients of the formulation and is not deleterious to the recipient thereof. According to another aspect of the invention, the method comprises mixing a compound or salt, solvate, etc. of formula (I) with one or more pharmaceutically acceptable carriers, diluents, or excipients. Also provided are methods for preparing pharmaceutical formulations.

  Certain protected derivatives of compounds of formula (I) may be made prior to the final deprotection step and may not have pharmacological activity per se, but in certain instances are oral Alternatively, those of skill in the art will appreciate that they can be administered parenterally and then metabolized in the body to form pharmacologically active compounds of the invention. Accordingly, such derivatives may be described as “prodrugs”. In addition, certain compounds of the invention can act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of the compounds of the invention are included within the scope of the invention. Further, when appropriate functional groups are present in the compounds of the present invention, it is understood that certain moieties known to those skilled in the art as “pro-moieties” may be placed on such functional groups. Those skilled in the art will understand. Preferred prodrugs for the compounds of the present invention include esters, carbonates, hemiesters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals and ketals. Is mentioned.

Treatment The compounds and pharmaceutical compositions of the invention are used to treat cell proliferative disorders. Conditions that can be treated by the methods and compositions herein include, but are not limited to, cancer (described further below), autoimmune disease, fungal disease, arthritis, graft rejection, inflammatory bowel disease, Include, but are not limited to, hyperplasia induced after medical procedures including surgery, angioplasty, and the like. It will be appreciated that in some cases the cells may not be in an abnormally high or abnormally low proliferative state (abnormal state) and may still require treatment. For example, during wound healing, cells can be “normally” grown, but enhanced growth may be desirable. Thus, in one embodiment, herein, the invention includes application to cells or individuals that are or are about to be affected by any one of these disorders or conditions.

  The compositions and methods provided herein are believed to be particularly useful for the treatment of cancers including tumors such as prostate, breast, brain, skin, cervical cancer, testicular cancer and the like. They are particularly useful for the treatment of metastases or malignant tumors. In particular, cancers that can be treated by the compositions and methods of the present invention include astrocytes, breast, cervix, colorectal, endometrium, esophagus, stomach, head and neck, hepatocytes, larynx, lung, oral cavity. Tumor types such as, but not limited to, ovarian, prostate and thyroid epithelial and non-epithelial malignancies. More specifically, these compounds are: heart: non-epithelial malignant tumor (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; Lung: Bronchiogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) epithelial malignant tumor, bronchial adenoma, non-epithelial malignant tumor, lymphoma, cartilage malpractice Gastrointestinal: Esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (epithelial malignant tumor, lymphoma, leiomyosarcoma), pancreas (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma) , Carcinoid tumor, VIP-producing tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma), leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, Tubular adenoma Villous adenoma, hamartoma, leiomyoma); urogenital tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, Adenocarcinoma), prostate (adenocarcinoma, non-epithelial malignant tumor), testis (seminal epithelioma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, non-epithelial malignant tumor, stromal cell carcinoma, fibroma, fiber Adenoma, adenoma-like tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, hemangiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, papillary cancer, bile duct cancer; bone : Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (Osteochronoma) (osteochondroma), benign chondroma, chondroblastoma, cartilage mucus fiber Chondromyxofibroma, osteoid and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteoarthritis), meninges (meningiomas, meningiosarcomas, glia) ), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineoplastoma), glioblastoma multiform, oligodendroglioma, nerve sheath Tumor, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, non-epithelial malignant tumor); gynecological system: uterus (endometrial cancer), cervix (cervical cervix) Cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, non-classifiable cancer), granulosa-heal cell tumors) ), Sertoli Leydig cell tumor, undifferentiated Celloma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, grapevine sarcoma (fetal rhabdomyosarcoma) , Fallopian tube (epithelial malignant tumor); blood system: blood (spinal leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplasia Syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, mole dysplastic nevi, lipoma, hemangioma, skin Fibroma, keloid, psoriasis; and adrenal gland: can be used to treat neuroblastoma. Thus, as provided herein, the term “cancer cell” includes cells affected by any one of the above-identified conditions or related conditions.

The compounds can be mixed or co-administered with other therapeutic agents, particularly agents that can improve the activity or pharmacokinetic time of the compound. Combination therapy according to the present invention comprises the administration of at least one compound of the present invention and the use of at least one other therapeutic method.
In one embodiment, the combination therapy described in the present invention comprises administration of at least one compound of the present invention, and surgical treatment. In one embodiment, the combination therapy according to the invention comprises the administration of at least one compound of the invention and radiation therapy. In one embodiment, the combination therapy described in the present invention comprises the administration of at least one compound of the present invention and at least one symptomatic drug (eg, at least one antiemetic). In one embodiment, the combination therapy according to the invention comprises the administration of at least one compound of the invention and at least one other chemotherapeutic agent. In one particular embodiment, the present invention comprises the administration of at least one compound of the present invention and at least one antitumor agent. In yet another embodiment, the invention provides that the EZH2 inhibitor of the present disclosure is not active or not significantly active by itself, but may not be active as a single therapy. When used in combination with a treatment, the combination comprises a treatment plan that provides a useful therapeutic result.

As used herein, the term “co-administer” and its derivatives are useful in cancer treatment, including compounds that inhibit EZH2 as described herein, and chemotherapy and radiotherapy. It is meant either the simultaneous administration of further active ingredients or ingredients known to be, or any sequential separate administration in any manner. As used herein, the term additional active ingredient or ingredient includes any compound or therapeutic agent that exhibits beneficial properties when administered to a patient known or in need of treatment for cancer.
Where administration is not simultaneous, it is preferred that the compounds be administered in close proximity to one another in time.
Furthermore, it does not matter whether the compounds are administered in the same dosage form, for example one compound can be administered topically and another compound can be administered orally.

Typically, any anti-tumor agent that has activity against the sensitive tumor being treated can be co-administered in the treatment of cancer identified in the present invention. Examples of such agents, Cancer Principles and Practice of Oncology by VT Devita and S. Hellman (editors), 6 th edition (February 15, 2001), can be found in Lippincott Williams & Wilkins Publishers. One of ordinary skill in the art will be able to determine which drug combinations are useful based on the relevant drugs and the specific nature of the cancer. Typical anti-tumor agents useful in the present invention include microtubule inhibitors such as diterpenoids and vinca alkaloids; platinum coordination compounds; nitrogen mustards, oxazaphosphorines, alkyl sulfonates, nitrosoureas, and triazenes Alkylating agents such as: antibiotics such as anthracyclines, actinomycin and bleomycin; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogs and antifolate compounds; Topoisomerase I inhibitors such as camptothecin; hormones and hormone analogs; DNA methyltransferase inhibitors such as azacitidine and decitabine; signaling pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; Agents; proapoptotic agents; and cell cycle signaling inhibitors including but not limited to.

  Typically, any chemotherapeutic agent that has activity against the sensitive neoplasm to be treated is of the present invention, provided that the particular agent is clinically compatible with treatment with a compound of the invention. It can be used in combination with a compound. Exemplary anti-tumor agents useful in the present invention include alkylating agents, antimetabolites, anti-tumor antibiotics, anti-mitotic agents, nucleoside analogs, topoisomerase I and II inhibitors, hormones and hormone analogs; Retinoids, histone deacetylase inhibitors; signaling pathway inhibitors, including inhibitors of cell proliferation or growth factor function, angiogenesis inhibitors, and serine / threonine or other kinase inhibitors; cyclin-dependent kinase inhibitors; Antisense and immunotherapeutic agents, including monoclonal antibodies, vaccines or other biological agents include but are not limited to these.

  Nucleoside analogs are compounds that are converted to deoxynucleotide triphosphates and incorporated into replicating DNA instead of cytosine. DNA methyltransferases covalently bind to modified bases, resulting in enzyme inactivation and reduced DNA methylation. Nucleoside analogs include, for example, azacitidine and decitabine used in the treatment of myelodysplastic syndromes. Histone deacetylase (HDAC) inhibitors include vorinostat for the treatment of cutaneous T-cell lymphoma. HDAC modifies chromatin through histone deacetylation. In addition, they have a variety of substrates including many transcription factors and signaling molecules. Other HDAC inhibitors are in development.

  Signal transduction pathway inhibitors are inhibitors that block or inhibit chemical processes that trigger intracellular changes. As used herein, this change is cell proliferation or differentiation or survival. Signal transduction pathway inhibitors useful in the present invention include receptor-type kinases, non-receptor-type kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphatidylinositol-3-OH kinase, myo-inositol signaling, and Ras oncogenes But are not limited to these. Signal transduction pathway inhibitors can be used in combination with the compounds of the present invention in the compositions and methods described above.

Receptor kinase angiogenesis inhibitors may also find use in the present invention. Inhibitors of angiogenesis related to VEGFR and TIE-2 are described above with respect to signaling inhibitors (both are receptor kinases). Other inhibitors can be used in combination with the compounds of the present invention. For example, which do not recognize VEGFR (the receptor kinase), anti-VEGF antibody that binds to the ligand; small molecule inhibitors that inhibit angiogenesis (alpha _v beta _3); endostatin and angiostatin endostatin and angiostatin (non-RTK) may also It can be seen that it is useful in combination with the compound of the present invention. An example of a VEGFR antibody is bevacizumab (Avastin ™).

  Several inhibitors of growth factor receptors are in development and include ligand antagonists, antibodies, tyrosine kinase inhibitors, antisense oligonucleotides and aptamers. Any of these growth factor receptor inhibitors can be used in combination with the compounds of the present invention in any of the compositions and methods / uses described herein. Trastuzumab (Herceptin ™) is an example of an anti-erbB2 antibody inhibitor of growth factor function. An example of an anti-erbB1 antibody inhibitor of growth factor function is cetuximab (Arbitux ™, C225). Bevacizumab (Avastin ™) is an example of a monoclonal antibody against VEGFR. Small molecule inhibitors of epidermal growth factor receptor include, but are not limited to, lapatinib (Tykerb ™) and erlotinib (Tarceva ™), for example. Imatinib mesylate (Gleevec ™) is one example of a PDGFR inhibitor. Examples of VEGFR inhibitors include pazopanib, ZD6474, AZD2171, PTK787, sunitinib and sorafenib.

  Anti-microtubules or anti-mitotic drugs are cell cycle specific agents that act as microtubules of tumor cells during the M phase or division phase of the cell cycle. Anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.

Diterpenoids derived from natural sources are cell cycle specific anticancer agents that act in the G ₂ / M phase of the cell cycle. Diterpenoids are thought to stabilize this protein by binding to the microtubule β-tubulin subunit. The protein degradation is then inhibited, mitosis is stopped, and cell death appears to occur subsequently. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.

Paclitaxel, 5β, 20-epoxy-1,2α, 4,7β, 10β, 13α-hexa-hydroxytaxa-11-en-9-one 4,10-diacetate 2-benzoate 13-ester and (2R , 3S) -N-benzoyl-3-phenylisoserine is a natural diterpene product isolated from the yew tree, Taxus brevifolia , and is commercially available as Taxol ™ for injection. Yes. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. (J. Am. Chem, Soc., 93: 2325. 1971) and they revealed their structure by chemical and X-ray crystallographic methods. . One mechanism of its action is related to the ability of paclitaxel to bind to tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77: 1561-1565 (1980); Schiff et al., Nature, 277: 665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981). For a review of the synthesis and anticancer activity of some paclitaxel derivatives: DGI Kingston et al., Studies in Organic Chemistry vol. 26, entitled “New trends in Natural Products Chemistry 1986”, Attaur-Rahman, PW Le Quesne, Eds (Elsevier, Amsterdam, 1986) See pp 219-235.

  Paclitaxel is a treatment for refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann. Lntem, Med., 111: 273,1989) And clinical use for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83: 1797, 1991). It includes skin neoplasms (Einzig et. Al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck cancer (Forastire et. Al., Sem. Oncol., 20:56, 1990). Is a promising candidate for treatment. The compound also shows potential for the treatment of polycystic kidney disease (Woo et. Al., Nature, 368: 750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel is associated with a dosing period exceeding the threshold concentration (50 nM) (Kearns, CM et. Al., Seminars in Oncology, 3 (6) p.16-23, 1995). multiple cell lineages, Ignoff, RJ et. al, Cancer Chemotherapy Pocket Guide, 1998).

  Docetaxel, (2R, 3S) -N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester and 5β-20-epoxy-1,2α, 4,7β, 10β, 13α-hexahydroxytax Sa-11-en-9-one 4-acetate 2-benzoate, trihydrate is commercially available as an injectable solution as Taxotere ™. Docetaxel is indicated for treatment in the treatment of breast cancer. Docetaxel is a semi-synthetic derivative of paclitaxel (qv.) Prepared using the natural precursor 10-deacetyl-baccatin III extracted from the needles of European yew trees. The dose limiting toxicity of docetaxel is neutropenia.

  Vinca alkaloids are anti-tumor agents specific to the cell cycle derived from periwinkle plants. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by specifically binding to tubulin. As a result, bound tubulin molecules cannot polymerize into microtubules. Mitosis is thought to stop at metaphase, followed by cell death. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.

  Vinblastine and vincaloycoblastine sulfate are commercially available as injections as Bellvan (trademark). Although it may be indicated as a second line treatment for various solid tumors, it is mainly indicated for the treatment of various lymphomas, including testicular cancer and Hodgkin's disease and lymphocytic and histiocytic lymphomas. Myelosuppression is a dose limiting side effect of vinblastine.

  Vincristine, vinca leucoblastin, 22-oxo-, sulfate are commercially available as injections as Oncobin ™. Vincristine is indicated for the treatment of acute leukemia and is also used in treatment regimens for Hodgkin and non-Hodgkin malignant lymphoma. Alopecia and neurological effects are the most frequent side effects of vincristine, with less frequent effects of myelosuppression and gastrointestinal mucositis.

Vinorelbine, 3 ', 4'-didehydro-4'-deoxy-C'-norvin caleucoblastin [R- (R ^* , R ^* )-], marketed as an injection of vinorelbine tartrate (Navelbine ™) 2,3-dihydroxybutanedioate (1: 2) (salt)] is a semi-synthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents such as cisplatin for the treatment of various solid tumors, particularly non-small cell lung, advanced breast cancer, and hormone refractory prostate cancer. Myelosuppression is the most common dose limiting side effect of vinorelbine.

  Platinum coordination compounds are anti-cancers that are non-specific to the cell cycle that interact with DNA. Platinum complexes enter tumor cells, undergo aqualation, and form intrastrand and interstrand crosslinks with DNA, causing deleterious biological effects on the tumor. Examples of platinum coordination compounds include, but are not limited to, cisplatin and carboplatin.

  Cisplatin, cis-diamminedichloroplatinum, is commercially available as an injectable solution as Platinol ™. Cisplatin is mainly indicated for the treatment of metastatic testicular cancer and ovarian cancer and advanced bladder cancer. The main dose limiting side effects of cisplatin are nephrotoxicity, which can be controlled by hydration and diuresis, and ototoxicity.

  Carboplatin, platinum, diammine [1,1-cyclobutane-dicarboxylate (2-)-O, O '] is commercially available as an injectable solution as Paraplatin ™. Carboplatin is indicated primarily for first-line and second-line treatment of advanced ovarian cancer. Myelosuppression is the dose limiting toxicity of carboplatin.

  Alkylating agents are anticancer drugs that are non-specific to the cell cycle and are strong electrophiles. Typically, alkylating agents form a covalent bond with DNA through nucleophilic moieties of DNA molecules such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups by alkylation. Such alkylation interferes with nucleic acid function and leads to cell death. Alkylating agents include, for example, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine. However, it is not limited to these.

Cyclophosphamide, 2- [bis (2-chloroethyl) amino] tetrahydro-2H-1,3,2-oxazaphospholine 2-oxide monohydrate is commercially available as CITOXAN ™ in injections or tablets Has been. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents for the treatment of malignant lymphoma, multiple myeloma, and leukemia.
Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.

  Melphalan, 4- [bis (2-chloroethyl) amino] -L-phenylalanine is marketed as Alkeran ™ in injections or tablets. Melphalan is indicated for palliative treatment of multiple myeloma and ovarian unresectable epithelial tumors. Myelosuppression is the most common dose limiting side effect of melphalan.

  Chlorambucil, 4- [bis (2-chloroethyl) amino] benzenebutanoic acid is commercially available as Leuqueran ™ tablets. Chlorambucil is indicated for palliative treatment of chronic lymphocytic leukemia and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Myelosuppression is the most common dose limiting side effect of chlorambucil.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available as Milleran ™ tablets. Busulfan is indicated for palliative treatment of chronic myelogenous leukemia.
Myelosuppression is the most common dose limiting side effect of busulfan.

  Carmustine, 1,3- [bis (2-chloroethyl) -1-nitrosourea, is commercially available as BiCNU ™ in a single vial of lyophilized material. Carmustine is indicated as a single agent or in combination with other drugs for palliative treatment of brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphoma. Delayed myelosuppression is the most common dose limiting side effect of carmustine.

  Dacarbazine, 5- (3,3-dimethyl-1-triazeno) -imidazole-4-carboxamide is commercially available in a single vial of material as DTIC-Dome ™. Dacarbazine is indicated for the treatment of metastatic melanoma and in combination with other drugs for second-line treatment of Hodgkin's disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.

  Antibiotic anti-neoplastic agents are agents that are nonspecific for the cell cycle that bind or intercalate with DNA. Typically, such actions result in stable DNA complexes or strand breaks that interfere with the normal function of the nucleic acid and lead to cell death. Antibiotic anti-tumor agents include, but are not limited to, for example, actinomycins such as dactinomycin, anthracyclines such as daunorubicin and doxorubicin; and bleomycin.

  Dactinomycin, also known as actinomycin D, is commercially available in injectable form as Cosmegen ™. Dactinomycin is indicated for the treatment of Wilms tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.

  Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl) oxy] -7,8,9,10-tetrahydro- 6,8,11-Trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride is commercially available in the injectable form of liposomes as DAUNOXOME ™ or as an injectable substance as CERUBIINE ™. Daunorubicin is indicated for induction of remission in the treatment of acute nonlymphocytic leukemia and advanced HIV-related Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.

  Doxorubicin, (8S, 10S) -10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl) oxy] -8-glycoloyl, 7,8,9,10-tetrahydro-6 , 8,11-Trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride is commercially available in injectable form as RUBEX ™ or Adriamycin RDF ™. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component for the treatment of several solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.

A cytotoxic glycopeptide antibiotic mixture isolated from bleomycin, a Streptomyces verticillus strain, is commercially available as Brenoxane ™. Bleomycin is indicated as a palliative treatment for squamous cell carcinoma, lymphoma, and testicular cancer as a single agent or in combination with other drugs. Pulmonary or skin toxicity is the most common dose limiting side effect of bleomycin.

  Topoisomerase II inhibitors include, but are not limited to epipodophyllotoxins.

Epipodophyllotoxins are cell cycle specific anti-tumor drugs derived from mandrake plants. Epipodophyllotoxins typically by forming a topoisomerase II and DNA ternary complex, act on cells in S phase and G ₂ phases of the cell cycle, cause DNA strand breaks. The strand breaks accumulate and cell death follows. Epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

  Etoposide, 4'-demethyl-epipodophyllotoxin 9 [4,6-0- (R) -ethylidene-β-D-glucopyranoside] is commercially available as VePESID ™ in injections or capsules, Generally known as VP-16. Etoposide is indicated for the treatment of testicular cancer and non-small cell lung cancer in combination with single agents or other chemotherapeutic agents. Myelosuppression is the most common side effect of etoposide. The occurrence of leucopenia tends to be more serious than thrombocytopenia.

  Teniposide, 4'-demethyl-epipodophyllotoxin 9 [4,6-0- (R) -tenylidene-β-D-glucopyranoside] is commercially available as an injectable solution as VUMON ™ and is generally a VM -Known as -26. Teniposide is indicated for the treatment of acute leukemia in children, either alone or in combination with other chemotherapeutic agents. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.

  Antimetabolite tumor drugs are specific to the cell cycle that act on the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis Antitumor drug. As a result, S phase does not progress and cell death follows. Antimetabolite anti-tumor agents include, but are not limited to, for example, fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

  5-Fluorouracil, 5-fluoro-2,4- (1H, 3H) pyrimidinedione is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is incorporated into both RNA and DNA. The result is typically cell death. 5-Fluorouracil is indicated for the treatment of breast, colon, rectal, stomach and pancreatic epithelial malignancies, either alone or in combination with other chemotherapeutic agents. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (furoxyuridine) and 5-fluorodeoxyuridine monophosphate.

  Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (1H) -pyrimidinone is commercially available as Cytosar-U ™ and is generally known as Ara-C. Cytarabine is believed to exhibit specificity in the S phase of the cell cycle by inhibiting DNA strand elongation by incorporating cytarabine at the ends into the extending DNA strand. Cytarabine is indicated for the treatment of acute leukemia in combination with single agents or other chemotherapeutic agents. Other cytidine analogs include 5-azacytidine and 2 ', 2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.

  Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL ™. Mercaptopurine exhibits specificity in the S phase of the cell cycle by inhibiting DNA synthesis by a mechanism not yet identified. Mercaptopurine is indicated for the treatment of acute leukemia in combination with single agents or other chemotherapeutic agents. Myelosuppression and gastrointestinal mucositis are the expected side effects at high doses of mercaptopurine. A useful mercaptopurine analog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione is commercially available as TABLOID ™. Thioguanine exhibits specificity in the S phase of the cell cycle by inhibiting DNA synthesis by a mechanism not yet identified.
Thioguanine is indicated for the treatment of acute leukemia in combination with single agents or other chemotherapeutic agents. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyl adenine, fludarabine phosphate, and cladribine.

  Gemcitabine, 2'-deoxy-2 ', 2'-difluorocytidine monohydrochloride (β-isomer) is commercially available as GEMZAR ™. Gemcitabine exhibits specificity in the S phase of the cell cycle by blocking cell development through the G1 / S phase boundary. Gemcitabine, in combination with cisplatin, is indicated for the treatment of locally advanced non-small cell lung cancer and alone for the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, platelet reduction, and anemia, is the most frequent dose limiting side effect of gemcitabine administration.

  Methotrexate, N- [4 [[(2,4-diamino-6-pteridinyl) methyl] methylamino] benzoyl] -L-glutamic acid, is commercially available as sodium methotrexate. Methotrexate exerts its effects on the cell cycle in the S phase by inhibiting DNA synthesis, repair, and / or replication through inhibition of the dyhydrofolic reductase required for purine nucleotides and thymidyl synthetic acids. Specific. Methotrexate is indicated for the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin lymphoma, and epithelial malignancies of the breast, head, neck, ovary and bladder, in combination with single agents or other chemotherapeutic agents. Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are the expected side effects of methotrexate administration.

  Camptothecin, including camptothecin and camptothecin derivatives, is available or under development as a topoisomerase I inhibitor. Camptothecin cytotoxic activity is believed to be related to its topoisomerase I inhibitory activity. Camptothecins include, but are not limited to, irinotecan, topotecan, and various optical forms of 7- (4-methylpiperazino-methylene) -10,11-ethylenedioxy-20-camptothecin described below.

  Irinotecan HCl, (4S) -4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy] -1H-pyrano [3 ′, 4 ′, 6,7] indolizino [ 1,2-b] quinoline-3,14 (4H, 12H) -dione hydrochloride is commercially available as an injectable solution as CAMPTOSAR ™.

  Irinotecan is a derivative of camptothecin that binds to the topoisomerase I-DNA complex with its active metabolite SN-38. Cytotoxicity is believed to occur as a result of unrepairable double strand breaks caused by the interaction of topoisomerase I: DNA: irinotecan or SN-38 triple complexes with replication enzymes. Irinotecan is indicated for the treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCl are myelosuppression including neutropenia and GI effects including diarrhea.

  Topotecan HCl, (S) -10-[(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1H-pyrano [3 ′, 4 ′, 6,7] indolidino [1,2-b] quinoline -3,14- (4H, 12H) -dione monohydrochloride is commercially available as injectable solution HYCAMTIN ™. Topotecan is a derivative of camptothecin that binds to the topoisomerase I-DNA complex and prevents religation of single-strand breaks caused by topoisomerase I in response to torsional distortion of the DNA molecule. Topotecan is indicated for second-line treatment of metastatic epithelial malignancies of ovarian cancer and small cell lung cancer. The dose limiting side effect of topotecan HCl is myelosuppression, mainly neutropenia.

  The pharmaceutical composition may be presented in unit dosage form containing a predetermined amount of active ingredient per unit dosage. Such a unit may be, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of formula (I) depending on the condition being treated, the route of administration, and the age, weight and condition of the patient. Or a pharmaceutical composition can be presented in unit dosage form containing a predetermined amount of active ingredient per unit dosage. Preferred unit dosage compositions are those containing a daily dose or sub-dose as described herein above of the active ingredient, or an appropriate fraction thereof. Furthermore, such pharmaceutical compositions can be prepared by any of the methods well known in the pharmaceutical art.

  The pharmaceutical composition may be any suitable route of administration, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral ( Subcutaneous, intramuscular, intravenous, or intradermal) routes may be applied. Such compositions can be prepared by any method known in the pharmaceutical art, for example, by combining a compound of formula (I) with a carrier or excipient.

  Pharmaceutical compositions applied for oral administration include capsules or tablets; powders or granules: solutions or suspensions in aqueous or non-aqueous liquids, edible foams or whips; or oil-in-water liquid emulsions or water-in-oil types It can be presented as a separate unit such as a liquid emulsion.

  Capsules are made by preparing a powder mixture as described above and filling formed gelatin shells. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. Disintegrants or solubilizers such as agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the drug when the capsule is ingested.

In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include natural sugars such as starch, gelatin, glucose, or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes. . Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. The powder mixture is preferably prepared by mixing the compound in powder form with the diluent or base described above, a binder such as carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone, a dissolution retardant such as paraffin, a quaternary salt. And / or adsorbents such as bentonite, kaolin, or calcium hydrogen phosphate. The powder mixture can be granulated in a tablet mold by adding stearic acid, stearate, talc, or mineral oil. The smoothed mixture is then tableted by compression. The compounds of the present invention are free flowing (free)
it can be mixed with an inert carrier and directly compressed into tablets without going through a granulation or slugging step. A transparent or opaque protective coating consisting of a shellac coating, a coating of sugar or polymer material, and a glossy coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

  Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form with a given quantity containing a predetermined amount of the compound of formula (I). Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic medium. Suspensions can be formulated by dispersing the compound in a non-toxic medium. Solubilizing and emulsifying agents such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavoring additives such as peppermint oil, or natural sweeteners or saccharin or other artificial sweeteners are also added be able to.

  Where appropriate, dosage unit pharmaceutical compositions for oral administration can be microencapsulated. The formulation can also be adjusted to extend or sustain release, for example, by coating or embedding particulate material with polymers, waxes, and the like.

  Pharmaceutical compositions adapted for rectal administration can be provided as suppositories or enemas.

  Pharmaceutical compositions adapted for intravaginal administration can be provided as vaginal suppositories, tampons, creams, gels, pastes, foams, or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injections that may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the intended recipient's blood and composition isotonic. Liquid, and aqueous and non-aqueous sterile suspensions which may contain suspending and thickening agents.
The pharmaceutical composition is provided in unit dose containers or multiple dose containers such as, for example, sealed ampoules and vials, and can be freeze-dried (lyophilized) just before use by adding a sterile liquid carrier such as water for injection. Can be saved in state. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

  In addition to the ingredients specifically mentioned above, the pharmaceutical composition may contain other drugs conventionally used in the art in view of the type of formulation of interest, eg suitable for oral administration It should be understood that things can include flavorings.

  The therapeutically effective amount of a compound of the invention will depend on many factors, including, for example, the intended recipient's age and weight, the exact condition and its severity requiring treatment, the nature of the formulation, and the route of administration. It will ultimately be at the discretion of the physician in charge of prescribing the drug. However, an effective amount of a compound of formula (I) for the treatment of anemia is generally in the range of 0.001-100 mg / kg recipient body weight per day, preferably per kg body weight per day. It will be in the range of 01-10 mg. For a 70 kg adult mammal, the actual amount per day will preferably be between 7 and 700 mg, which may be given once a day and the total daily dose is Several (2, 3, 4, 5 or 6) sub-doses may be given per day to be the same. An effective amount, such as a salt or solvate, can be determined as a proportion of the effective amount of the compound of formula (I) itself. It is envisioned that similar dosages will be appropriate for the treatment of other conditions mentioned above.

Chemical Background The compounds of the present invention can be made by a variety of methods, including standard chemistry. All previously defined variables will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention that are prepared are shown in the Examples.

  The compounds of general formula (I) may be prepared by methods known in the field of organic synthesis, partially shown in the following synthetic schemes. In all of the schemes described below, it is well understood that protecting groups are used for sensitive or reactive groups where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes, as well as the reaction conditions and their order of execution, shall be consistent with the preparation of compounds of formula (I). One skilled in the art will recognize whether a stereocenter exists in the compounds of formula (I). Thus, the present invention includes both possible stereoisomers and includes individual enantiomers as well as racemates. Where it is desired that the compound be a single enantiomer, it can be obtained by stereospecific synthesis, or resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be performed by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

General Experimental Methods Throughout the experiments, the following abbreviations are used and have the following meanings:
aq aqueous / aqueous solution BINAP 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl
ca. About CDCl ₃ -d chloroform-d
CD ₃ OD-d ₄ Methanol-d ₄
Cs ₂ CO ₃ Cesium carbonate CHCl ₃ Chloroform ACN Acetonitrile CH ₃ CN Acetonitrile Celite ™ Celite Corporation brand diatomite trademark DBU 1,8-diababicyclo [5.4.0] undec-7-ene DCE dichloroethane DCM Methylene chloride DME 1,2 Dimethoxyethane DMF N, N-dimethylformamide DIEA Diisopropylethylamine DMSO-d ₆ Dimethylsulfoxide-d ₆
EtOAc ethyl acetate EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride h time
¹ H NMR proton nuclear magnetic resonance HCl HCl HOAT 1-hydroxy-7-azabenzotriazole HPLC high performance liquid chromatography IPA 2-propanol K ₂ CO ₃ potassium carbonate KOH potassium hydroxide LC / MS liquid chromatography / mass spectrometry MgSO ₄ sulfuric acid Magnesium MeOH Methanol Min Minute MTBE Methyl tert-butyl ether MS Mass spectrometry NaOH Sodium hydroxide Na ₂ SO ₄ Sodium sulfate NH ₄ OH Ammonium hydroxide NMM 4-Methylmorpholine NMP N-methyl-2-pyrrolidone Pd / C Palladium (10 wt% ) carbon _{PdCl 2 (dppf) -CH 2 Cl} 2 1,1'- bis (diphenylphosphino) ferrocene - palladium dichloride (II) - dichloromethane complex d _(Ph 3 _{P) 4} tetrakis (triphenylphosphine) palladium (0)
SOCl ₂ thionyl chloride SPhos 2-dicyclohexylphosphino-2 ', 6'-dimethoxy biphenyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography

The following guidelines apply to all of the experimental procedures described herein.
All reactions were performed under positive pressure nitrogen using oven-dried glassware unless otherwise indicated. The specified temperature is the approximate temperature of the outside (ie bath temperature). Air and moisture affected liquids were transferred by syringe. The reagent was used as is. The solvent used was that described as “anhydrous” by the supplier. The molar concentration for the active reagent in solution was approximate and was used without pre-titration against the corresponding standard. All of the reactions were agitated with a stir bar unless otherwise indicated. Heating was done using a heat bath containing silicone oil unless otherwise indicated. Reactions performed by microwave irradiation (0-400 W at 2.45 GHz) consisted of a Biotage Initiator ™ 2.0 instrument, a Biotage microwave EXP vial (0.2-20 mL) and a septum and lid. Made using. The irradiation level utilized (ie, high, normal, low) based on solvent and ionic charge was based on the supplier's specifications. Cooling to temperatures below −70 ° C. was done using dry ice / acetone or dry ice / 2-propanol. Magnesium sulfate and sodium sulfate used as desiccants were anhydrous grades and were used interchangeably. Solvents described as being removed “under vacuum” or “under reduced pressure” were made so by rotary evaporation.

  Preparative normal phase silica gel chromatography was performed using a Teledyne ISCO CombiFlash Companion instrument equipped with RediSep or ISCO Gold silica gel cartridges (4 g-330 g), or an Analogix IF280 instrument equipped with SF25 silica gel cartridges (4 g-300 g), or HP silica gel. This was performed using any of the Biotage SP1 instruments equipped with cartridges (10 g to 100 g). Purification by reverse phase HPLC was performed using a YMC-pack column (ODS-A75 × 30 mm) as the solid phase unless otherwise specified. Unless otherwise noted, 25 mL / min A (acetonitrile-0.1% TFA): B (water-0.1% TFA), 10-80% gradient A (10 min) mobile phase and UV at 214 nM. Detection was used.

A PE Sciex API 150 single quadrupole mass spectrometer (PE Sciex, Thornhill, Ontario, Canada) was operated using electrospray ionization in positive ion detection mode. The atomization gas was generated from a zero air generator (Balston Inc., Haverhill, Mass., USA) and sent at 65 psi, and the curtain gas was high purity nitrogen delivered at 50 psi from a Dewar liquid nitrogen vessel. The voltage applied to the electrospray needle was 4.8 kV.
The orifice was set at 25 V and the mass spectrometer was scanned at a rate of 0.5 scan / sec with the profile data collected using a step mass of 0.2 amu.

Method A LCMS. Samples were introduced into the mass spectrometer using a CTC PAL autosampler (LEAP Technologies, Carrboro, NC) equipped with a Hamilton 10 μL syringe injecting into a Valco 10 port-injection valve.
The HPLC pump is Shimadzu LC-10ADvp (Shimadzu Scientific Instruments, Columbia, Md.), 0.3 mL / min, a 4.5% A to 90% B linear in 3.2 minutes Operated with gradient and 0.4 min hold. The mobile phase consisted of 100% of vessel A (H ₂ O 0.02% TFA) and 100% of vessel B (CH ₃ CN 0.018% TFA). The stationary phase was Aquasil (C18) and the column dimensions were 1 mm × 40 mm. Detection was by 214 nm UV, evaporative light scattering (ELSD) and MS.

Method B LCMS. Alternatively, use an Agilent 1100 analytical HPLC system with LC / MS, with a linear gradient from 5% A to 100% B and hold at 0.4 min at 1 mL / min and 2.2 min. Operated. The mobile phase consisted of 100% of vessel A (H ₂ O 0.02% TFA) and 100% of vessel B (CH ₃ CN 0.018% TFA). The stationary phase was Zobax (C8) with a particle size of 3.5 μm and the column dimensions were 2.1 mm × 50 mm. Detection was by 214 nm UV, evaporative light scattering (ELSD) and MS.

Method C LCMS. As an alternative method, MDS SCIEX API 2000 equipped with a capillary column (50 × 4.6 mm, 5 μm) was used. HPLC was performed on an Agilent-1200 series UPLC system equipped with a column Zorbax SB-C18 (50 × 4.6 mm, 1.8 μm) eluting with CH ₃ CN: ammonium acetate buffer. The reaction was performed in the microwave (CEM, Discover).

¹ H-NMR spectra were recorded at 400 MHz using a Bruker AVANCE 400 MHz instrument, and an ACD Spec manager ver10 was used for reprocessing. The multiplicity shown is: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sxt = sexualt, m = multiplet, dd = doublet doublet, dt = triplet doublet, etc. br indicates a broad signal.

Analytical HPLC: equipped with a 4.5 × 75 mm Zorbax XDB-C18 column (3.5 μm), 2% / min and 5% CH ₃ CN (0.1% formic acid) in H ₂ O (0.1% formic acid) The product was analyzed on an Agilent 1100 analytical chromatography system using a 4 minute gradient from 1 to 95% CH ₃ CN (0.1% formic acid) and a 1 minute hold.

  The compounds of the invention are prepared according to the following schemes 1-4 described in detail below. In the following, the groups and substituents shown in Schemes 1-4 such as X, Y, Z and various R groups have the same definitions as they have herein before. The solvents and conditions mentioned are exemplary and are not intended to be limiting.

Scheme 1

Scheme 1 illustrates two methods for synthesizing compounds of formula (VII). The substituted aminopyrazole of formula (I) is heated with diethyloxobutanedione in benzene or toluene at 62 ° C. overnight. Treatment of the expected intermediate with acetic acid and heating at typical reflux yields the azaindazole compound of formula (II). The compound of formula (II) is converted to the compound of formula (III) by base catalyzed hydrolysis of the ethyl ester, followed by chlorination of the expected carboxylic acid intermediate with POCl ₃ under standard conditions, The compound of IV) is obtained. Stir for over 12 hours using EDC, HOAT, N-methylmorpholine, and DMSO, typically at room temperature (in some cases, heating at 40 ° C. may be required), Treatment of a compound of formula (IV) with a substituted aminomethylpyridone of V) provides a compound of formula (VI). The compound of formula (VI) is substituted at the 6-position using standard methods known to those skilled in the art (ie nucleophilic substitution, palladium catalyzed cross-coupling) to give the compound of formula (VII). Alternatively, a compound of formula (VII) can be obtained from a compound of formula (II) via compounds (IIa) and (IVa). In this route, the compound of formula (II) is converted to the corresponding triflate (IIa) using standard methods. The compound of formula (IIa) is then substituted at the 6-position using standard palladium-catalyzed cross-coupling conditions, followed by hydrolysis of the ethyl ester group of the base catalyst to give the compound of formula (IVa) obtain. Stir at room temperature for more than 12 hours using EDC, HOAT, N-methylmorpholine, and DMSO at room temperature, treating the compound of formula (IVa) with a substituted aminomethylpyridone of formula (V) VII) is obtained.

Scheme 2

  Compounds of formula (VII) are also prepared as shown in Scheme 2. In this embodiment, a substituted oxobutanedione of formula (VIII) (prepared by Claisen condensation between a suitable substituted ketone and diethyl oxalate) is converted to a substitution of formula (I) (as described in Scheme 1). Heat with aminopyrazole to obtain the compound of formula (IX). The compound of formula (IX) is converted to the compound of formula (X) by base-catalyzed hydrolysis. Each substitution is carried out using methods known to those skilled in the art (eg bromination, nitration) at either the R3 position or the R6 substituent of the compounds of formula (IX) and (X). At room temperature, EDC, HOAT, N-methylmorpholine, and DMSO are used for at least 12 hours at room temperature and the compound of formula (X) is treated with a substituted aminomethylpyridone of formula (V) to give the formula ( VII) is obtained.

Scheme 3

Compounds of formula (VII) are also prepared as shown in Scheme 3. In this embodiment, the substituted aminopyrazole of formula (I) is heated at 62 ° C. overnight in benzene containing a keto ester of formula (XI) and catalytic acetic acid. The expected intermediate is exposed to refluxing dawsam A overnight to give the compound of formula (XII). Non-commercial compounds of formula (XI) are prepared using standard methods known to those skilled in the art and are described herein. The compound of formula (XII) is converted to the compound of formula (XIII) by bromination with refluxing POBr ₃ in toluene / DMF for 1 hour. A compound of formula (XIII) is heated with dicyanozinc, tris (dibenzylideneacetone) dipalladium (0), and SPhos in DMF and water at 120 ° C. for 2 hours to give a compound of formula (XIV). The compound of formula (XIV) is hydrolyzed to the compound of formula (X) using standard base catalyzed hydrolysis conditions.

  Stir at room temperature for at least 12 hours at room temperature using EDC, HOAT, N-methylmorpholine, and DMSO, treat the compound of formula (X) with the substituted aminomethylpyridone of formula (V), ) Is obtained.

Scheme 4

Scheme 4 illustrates two methods for synthesizing compounds of formula (V). The compound of formula (XV) is heated at reflux containing cyanoacetamide and catalytic piperidine in ethanol, typically 30 minutes, to give the compound of formula (XVII). Alternatively, the compound of formula (XVII) can be treated with cyanoacetamide for about 90 minutes in DMSO in an atmosphere of oxygen at room temperature with an excess of potassium tert-butoxide to obtain a compound of formula (XVII) can get. The mixture of regioisomers is resolvable and the regiochemical assignment of individual compounds can be confirmed by 2D HNMR techniques. Non-commercial compounds of formulas (XV) and (XVI) are prepared using standard methods known to those skilled in the art and are described herein. By either hydrogenation using sodium acetate, palladium on carbon and platinum oxide, or reduction conditions using NaBH ₄ r with either iodine or NiCl ₂ -6H ₂ O, the compound of formula (XVII) is It can be converted to a compound of formula (V).

Example Intermediate 1
6-Hydroxy-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Step 1:
1- (1-Methylethyl) -1H-pyrazol-5-amine

To a solution of ethyl (2Z) -2-cyano-3- (ethyloxy) -2-propenoate (114.2 g, 0.67 mol) in ethanol (250 mL), isopropylhydrazine (55 g, 0.74 mol) was added dropwise. Slowly added. The mixture was heated at reflux for 4 hours and then cooled to room temperature. The mixture was concentrated under vacuum. Approximately half of the crude 5-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (50 g) was suspended in aqueous sodium hydroxide (4M, 130 mL) and stirred for 2 hours while heating at reflux. . The reaction mixture was then cooled to room temperature and adjusted to pH = 3.5 with conc. HCl, resulting in precipitate formation. The solid was collected by filtration and dried in a vacuum oven overnight to give crude 5-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid (30 g). The solid was suspended in diphenyl ether (120 mL) and stirred for 2 hours while heating at 160-165 ° C. The solution was then cooled to room temperature and the solvent was removed under vacuum. The crude product was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 1: 1) to give 12 g of product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.24 (d, 6H, J = 6.4 Hz), 4.32 (m, 1H), 5.06 (s, 2H), 5.21 ( s, 1H), 7.00 (s, 1H).

Step 2:
To a solution of diethyl 2-oxobutanedione (96 g) in toluene (500 mL) was added 1- (1-methylethyl) -1H-pyrazol-5-amine (30 g, 0.24 mol) and the mixture was heated at 60 ° C. Stir overnight. The mixture was concentrated in vacuo and the crude residue was dissolved in acetic acid (500 mL) and then heated at reflux for 2 hours. The mixture was then cooled to room temperature and concentrated in vacuo to give a residue that was recrystallized from DCM and the product was collected to give 40 g of a yellow solid. This solid was suspended in ethanol (700 mL) and THF (100 mL), followed by addition of 3M NaOH (150 mL). The reaction mixture was stirred at 40 ° C. for 40 minutes. The mixture was concentrated in vacuo to remove volatiles and then the aqueous layer was acidified using 1M HCl. The resulting precipitate was collected by filtration and dried under high vacuum to give the title compound, 6-hydroxy-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4. -27 g of carboxylic acid were obtained. LCMS ES (M + H) = 222.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.48 (d, J = 6.82 Hz, 6H), 4.89-4.96 (m, 1H), 6.81 (s, 1H), 8.13 (s, 1H).

Intermediate 2
3-Methyl-1- (1-methylethyl) -6-oxo-6,7-dihydro-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Step 1:
3-Methyl-1- (1-methylethyl) -1H-pyrazol-5-amine

3-Amino-2-butenenitrile (33.3 g, 0.41 mol) and ethanol (170 mL) were combined and stirred at room temperature for 30 minutes, after which isopropylhydrazine (50 g, 0.67 mol) was added in one portion. After stirring at room temperature for 5 minutes, the contents were then heated at reflux for 10 hours. After cooling to room temperature, the mixture was concentrated in vacuo to give the desired product (85 g) that was used as such in the next step. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.21 (d, 6H, J = 6.4 Hz), 1.94 (s, 3H), 4.21 (m, 1H), 4.93 (s, 2H), 5.02 (s, 1H).

Step 2:
To a solution of diethyl 2-oxobutanedione (176 g, 0.94 mol) in toluene (2 L) was added 3-methyl-1- (1-methylethyl) -1H-pyrazol-5-amine (82.5 g,. 59 mol) was added and the mixture was stirred at 62 ° C. overnight. After cooling to room temperature, the mixture was concentrated in vacuo and the crude residue was dissolved in acetic acid (1.5 L). The mixture was heated at reflux for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo to give a solid residue that was recrystallized from DCM to give the desired product as a yellow solid. The collected solid was suspended in ethanol (1510 mL) and THF (216 mL) followed by 3N NaOH (334 mL) and the reaction mixture was stirred at 40 ° C. for 40 min. The mixture was concentrated in vacuo to remove volatiles and the aqueous phase was acidified using 1N HCl. The resulting precipitate was collected by filtration, dried under high vacuum, and the title compound, 3-methyl-1- (1-methylethyl) -6-oxo-6,7-dihydro-1H-pyrazolo [ There were obtained 51.38 g of 3,4-b] pyridine-4-carboxylic acid. LCMS ES (M + H) = 236.1. ¹ H
NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.35 (d, J = 6.8 Hz, 6H), 2.41 (s, 3H), 4.84-4.91 (m, 1H), 6.64 ( s, 1H).
Carboxylic acid proton, not observed.

Intermediate 3
Ethyl 1- (1,1-dimethylethyl) -6-hydroxy-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

1- (1,1-dimethylethyl) -3-methyl-1H-pyrazol-5-amine (5 g, 32.6 mmol), diethyl 2-oxobutanedione (6.14 g, 32.6 mmol) and toluene (100 mL) Was heated at 70 ° C. for 16 hours. The solvent was removed under vacuum and the crude residue was dissolved in acetic acid (100 mL) and heated at reflux for 4 hours. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography (eluent: gradient 0-10% EtOAc / hexanes). The product was recovered as 6.32 g (70%) solid. LCMS ES (M + H) = 278.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.39 (s, 1H), 6.82 (s, 1H), 4.36 (q, 2H, J = 7.2 Hz), 2.45 ( s, 3H), 1.69 (s, 9H), 1.32 (t, 3H, J = 7.2 Hz).

Intermediate 4
1- (1,1-Dimethylethyl) -6-hydroxy-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Sodium hydroxide (52.6 mL, 52.6 mmol) was added to ethyl 1- (1,1-dimethylethyl) -3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo [3,4-b]. To a solution of pyridine-4-carboxylate (7.3 g, 26.3 mmol) in EtOH (100 mL) was stirred at room temperature for 16 hours. The solvent was removed under vacuum. The crude residue was suspended in water and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO ₄ , filtered and concentrated under vacuum. The resulting solid product was saved. The aqueous phase was concentrated under vacuum and the crude product was purified by reverse phase HPLC (mobile phase: 20-50% ACN / H ₂ O, 0.1% TFA) to give additional product. The combined product was recovered as a solid 5.76 g (88%). LCMS ES (M + H) = 250.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.5-13.9 (brs, 1H), 11.2-11.5 (brs, 1H), 6.78 (s, 1H), 2. 46 (s, 3H), 1.70 (s, 9H).

Intermediate 5
6-Chloro-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

In a 75 mL pressure vessel, 1- (1-methylethyl) -6-oxo-6,7-dihydro-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (4.12 g, 18.62 mmol). Addition was followed by phosphorus oxychloride (26.0 mL, 279 mmol). The flask was sealed and the stirred mixture was heated at about 105 ° C. for about 18 hours. After cooling to room temperature, the contents were concentrated in vacuo to remove most of the volatile material. The remaining contents were poured into a mixture of ice and 3M NaOH (60 mL) followed by 3M NaOH to ensure that the pH remained acidic. The mixture was stirred for 30 minutes and then cooled in an ice bath. The heterogeneous mixture was slowly acidified with 6M HCl to pH = 3-4. The resulting suspension was extracted with EtOAc (3x). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under vacuum to give a yellow solid that was dried in a high vacuum oven overnight. 4.11 g (90%) of the title compound was recovered and used without further purification. LCMS ES (M + H) = 240.2 / 242.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.51 (d, J = 6.57 Hz, 6H) 5.17 (quin, J = 6.63 Hz, 1H) 7.65 (s, 1H) 8 .41 (s, 1H) 14.25 (br.s., 1H).

Intermediate 6
6-Chloro-3-methyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

3-methyl-1- (1-methylethyl) -6-oxo-6,7-dihydro-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (1.5 g, 6.38 mmol), To a solution of THF (15 mL) was added followed by phosphorus oxychloride (8.9 mL, 96 mmol) and the contents were heated at 105 ° C. overnight. After cooling to room temperature, the contents were concentrated in vacuo to remove most of the volatile material. The remaining contents were slowly poured into a solution of ice water and 1N NaOH (10 mL) and the contents were stirred at room temperature for 24 hours, during which time solid precipitation occurred.
Additional 1N NaOH was added, during which the solid dissolved in the solution. After being stirred at room temperature for 30 minutes, the contents were cooled in an ice bath and the mixture was slowly acidified to pH = 3-4 by slowly adding 6N HCl to give a heterogeneous mixture. The mixture was filtered and a white solid was saved. The aqueous layer was further extracted with EtOAc and DCM. The combined organic layer was dried over MgSO ₄ , filtered and concentrated under vacuum. The resulting light brown solid was triturated in EtOAc / EtOH (1: 1) and filtered to give an initial portion of a white solid product that was saved. The filtrate was again concentrated under vacuum. The residue was diluted with EtOAc, sonicated, treated with hexane and filtered. The process was repeated. The isolated solid product crop was dried under vacuum (3 hours) and recovered 1.33 g (80%). LCMS ES (M + H): 254.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.46 (d, 6H), 2.60 (s, 3H), 5.10 (quin, J = 6.63 Hz, 1H), 7.50 ( s, 1H), 14.17 (br.s., 1H).

Intermediate 7
6-Chloro-1- (1,1-dimethylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

1- (1,1-Dimethylethyl) -3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (5.07 g, 20.34 mmol) And phosphorus oxychloride (28.4 mL, 305 mmol) were heated at 100 ° C. for 16 h. The contents were concentrated under vacuum. The residue was added to ice water followed by 1N NaOH until basic (pH> 10). After stirring for 15 minutes, the mixture was adjusted to pH 3-4 by adding 1N HCl. The contents were extracted with EtOAc, then washed with water, brine and concentrated under vacuum. The crude product was purified by reverse phase _{HPLC (40~70% ACN / H 2} O, 0.1% TFA) and purified by. The product was recovered as 0.50 g (9%) of solid. LCMS ES (M + H) = 268.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.73 (s, 9H), 2.56 (s, 3H), 7.48 (s, 1H) 14.17 (br.s., 1H).

Intermediate 8
3- (Aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone hydrochloride

Sodium acetate (10.24 g, 124.8 mmol), 10% palladium on carbon (1.08 g) was placed in a Parr bottle dried under a nitrogen atmosphere and a small amount of acetic acid was added to wet the catalyst. Next, 4,6-dimethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (10 g, 67.6 mmol) in acetic acid was added to the pearl bottle, and more acetic acid was added. Cover the bottle with a pearl device (Parr
and shaken under a hydrogen atmosphere (45 psi) for 12 hours. The reaction mixture was filtered. The solvent was removed and a residue was obtained and dried. After the addition of 150 mL concentrated HCl, the solid formed was filtered. The yellow filtrate was concentrated and dried, then 10 mL concentrated HCl and 50 mL EtOH were added. The mixture was stored at about 0 ° C. (ie freezer) for 2 hours. The solid that formed was filtered, washed with cold EtOH, ether and dried to give the product as the HCl salt (39 g, 76%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.85 (brs, 1H) 8.13 (brs, 3H) 5.93-6.01 (m, 1H) 3.72-3.80 (m , 2H) 2.22 (s, 3H) 2.16 (s, 3H).

Intermediate 9
3- (Aminomethyl) -6-methyl-4- (trifluoromethyl) -2 (1H) -pyridinone

In a dry, 500 mL Parr bottle with a nitrogen inlet, sodium acetate (1.502 g, 18.30 mmol), 10% palladium on carbon (1.579 g, 0.742 mmol), platinum (IV) oxide (0 0.011 g, 0.049 mmol) and a small amount of acetic acid, and moistened the catalyst under a stream of nitrogen. Then 2-hydroxy-6-methyl-4- (trifluoromethyl) -3-pyridinecarbonitrile (2.0 g, 9.89 mmol) was added followed by acetic acid (175 mL) under a nitrogen atmosphere. The contents were sealed and placed on a pearl shaker and allowed to react with 40 psi H ₂ for about 6 hours, keeping H ₂ psi between 20 and 40 psi (the container was refilled twice).
The vessel was purged with nitrogen, the reaction mixture was filtered through celite, and the filter pad was washed with a small amount of acetic acid. Volatiles were removed in vacuo to give a residue that was dried under high vacuum for 45 minutes. The solid was suspended in concentrated HCl (12 mL), stirred and filtered (NaCl removed). The clear filtrate was concentrated under vacuum and the residue was dried under high vacuum. The collected solid was suspended in concentrated HCl (2 mL) and diluted with EtOH (13 mL). The contents were agitated (ie, spatula) and stored at about 0 ° C. (ie, freezer) for 30 minutes to give a white solid. The solid was filtered and washed with cold ethanol (5 mL). The solid was filtered and dried in a vacuum oven for 1 hour. 0.95 g (40%) of the final product was recovered. LCMS ES (M + H) = 206.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm
2.31 (s, 3H), 3.87 (d, J = 0.05 Hz, 2H), 6.41 (s, 1H), 8.12-8.37 (m, 3H).

Intermediate 10
3- (Aminomethyl) -4-cyclohexyl-6-methyl-2 (1H) -pyridinone

Process 1
To a stirred suspension of CrCl ₂ (58 g, 472.8 mmol in THF, 1500 mL) was added 1,1-dichloro-2-propanone (10 g, 78.8 mmol) and cyclohexanecarbaldehyde (8.84 g, 78.8 mmol). In THF (500 mL) was added. The reaction mixture was heated at reflux for 2 hours and then quenched by adding 1.0 M HCl. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The crude residue (10 g) was added to a solution of DMSO (150 mL) containing t-BuOK (7.5 g, 65.7 mmol), cyanoacetamide (6.1 g, 72.3 mmol) and stirred at room temperature for 30 minutes. Additional t-BuOK (22.5 g, 197.1 mmol) was added and the reaction mixture was stirred for an additional hour under an atmosphere of oxygen. The contents were purged with argon, diluted with 4 volumes of H ₂ O, and then 5 volumes of 4N HCl were slowly added. The reaction mixture was filtered, washed with water and dried to give 4.5 g (32%) of 4-cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.25 (s, 1H), 2.61-2.65 (m, 1H), 2.22 (s, 3H), 1.66-1. 79 (m, 4H), 1.24-1.46 (m, 6H).

Process 2
To a solution of the product from Step 1 (2 g, 9.26 mmol) in THF (100 mL), cooled in an ice bath, NaBH ₄ (0.81 g, 21.3 mmol), and I ₂ (2.3 g, 9.26 mmol). ) And the mixture was stirred for 30 minutes. The reaction mixture was then heated at reflux for 3 hours and cooled to room temperature. After cooling to 0 ° C., the reaction mixture was acidified by slowly adding 3N HCl (1 mL). The reaction mixture was concentrated in vacuo and the crude product was purified by reverse phase HPLC to give the title compound as a solid (TFA salt), 0.5 g (25%). LCMS ES (M + H) = 221.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.8-11.9 (brs, 1H), 7.80-7.93 (brs, 3H), 6.07 (s, 1H), 3. 69 (s, 2H), 2.67-2.75 (m, 1H), 2.17 (s, 3H), 1.58-1.72 (m, 5H), 1.19-1.41 ( m, 5H).

Intermediate 11
3- (Aminomethyl) -4-cyclopropyl-6-methyl-2 (1H) -pyridinone hydrochloride

A method similar to that described for intermediate 10 (step 2) from 4-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (5 g, 28.7 mmol). The title compound was prepared. The product was recovered as a TFA salt, 0.50 g. LCMS ES (M + H) = 179.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.76-11.78 (brs, 1H), 7.82-7.92 (brs, 3H), 5.61 (s, 1H), 3.94- 3.99 (m, 2H), 2.11 (s, 3H), 1.98-2.05 (m, 1H), 0.95-1.01 (m, 2H), 0.74-0. 79 (m, 2H).

Intermediate 12
3- (Aminomethyl) -6-methyl-4-propyl-2 (1H) -pyridinone

Process 1
To a solution of DMSO (300 mL) containing t-BuOK (20 g, 178 mmol) and cyanoacetamide (16.5 g, 196 mmol), (3E) -3-hepten-2-one (20 g, 178 mmol) was added and the contents Was stirred at room temperature for 30 minutes. Additional t-BuOK (60 g, 534 mmol) was added and the reaction mixture was placed under an atmosphere of oxygen for an additional hour. The reaction mixture was purged with argon, diluted with 4 volumes of H ₂ O, and then 5 volumes of 4N HCl were slowly added. The reaction mixture was filtered, washed with water and dried to give 10 g (32%) of product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.25-12.40 (brs, 1H), 6.18 (s, 1H), 2.53 (t, 2H), 2.22 (s, 3H), 1.57-1.64 (m, 2H), 0.84 (t, 3H).

Process 2
The title compound was prepared from the product of Step 1 (2 g, 11.2 mmol) in a manner similar to that described for Intermediate 10 (Step 2). 1.2 g (60%) of product was recovered. LCMS ES (M + H) = 181.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.85-7.95 (brs, 3H), 5.99 (s, 1H), 3.80-3.85 (m, 2H), 2. 42 (t, 2H), 2.14 (s, 3H), 1.43-1.49 (m, 2H), 0.86 (t, 3H).

Intermediate 13
3- (Aminomethyl) -6-methyl-4-phenyl-2 (1H) -pyridinone

The title compound was prepared from (3E) -4-phenyl-3-buten-2-one (20 g, 137 mmol) in a manner similar to that described for Intermediate 12 (Steps 1 and 2). 10 g (35%) of the crude nitrile intermediate was obtained and 4 g of this expected intermediate was converted to 1.2 g of the title compound as a TFA salt. LCMS ES (M + H) = 215.0. ¹ H
NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.2-12.3 (brs, 1H), 7.88-8.00 (brs, 3H), 7.43-7.51 (m, 3H), 7. 29-7.38 (m, 2H), 6.08 (s, 1H), 3.67-3.70 (m, 2H), 2.23 (s, 3H).

Intermediate 14
3- (Aminomethyl) -6-methyl-4- (1-methylethyl) -2 (1H) -pyridinone

The title compound was prepared from (3E) -5-methyl-3-hexen-2-one (20 g, 137 mmol) in a manner similar to that described for Intermediate 12 (Steps 1 and 2). 7 g (22%) of the crude nitrile intermediate was obtained and 3 g of this expected intermediate was converted to 1.3 g of the title compound as a TFA salt. LCMS ES (M + H) = 181.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.8-11.9 (brs, 1H), 7.86-7.96 (brs, 3H), 6,. 10 (s, 1H), 3.82-3.86 (m, 2H), 3.02-3.09 (m, 1H), 2.17 (s, 3H), 1.08 (d, 6H) .

Intermediate 15
3- (Aminomethyl) -4-methyl-6-propyl-2 (1H) -pyridinone

Process 1
At 30 ° C., a mixture of ethyl butyrate (50 g, 431 mmol) and acetone (37.5 g 646.5 mol) was added dropwise to a solution of NaNH ₂ (32.5 g, 862 mmol) in anhydrous ether (500 mL). After the addition, the reaction mixture was stirred for 4 hours. The reaction mixture was poured into ice water with stirring. Additional ether was added and the layers were separated. The aqueous layer was acidified to pH 5.0 with 2N HCl and then brought to pH 7.5 with Na ₂ CO ₃ . The aqueous layer was then extracted with ether. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The crude product (20 g, 156 mmol) and 2-cyanoacetamide (13.12 g, 156 mmol) were suspended in EtOH (160 mL) at 75 ° C. followed by the addition of piperidine (13.2 g, 156 mmol). The contents were stirred and heated at reflux for 1 hour. The mixture was cooled to room temperature and filtered. The collected solid was suspended in water and stirred for 1 hour. The mixture was filtered and dried to give 4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinecarbonitrile (11 g, 40%). LCMS ES (M + H) = 181.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.3-12.4 (brs, 1H), 6.25 (s, 1H), 3.64 (s, 3H), 2.50 (t, 2H), 1.63 (m, 2H), 0.94 (t, 3H).

Process 2
Sodium acetate (3.5 g, 42.6 mmol), palladium on carbon (0.81 g) and platinum oxide (0.1 g) are placed in a dry pearl bottle (Parr bottle) flushed with nitrogen followed by a small amount of acetic acid. Was added (to wet the catalyst). A solution of 4-methyl-2-oxo-6-propyl-1,2-dihydro-pyridine-3-carbonitrile (5 g, 28 mmol) in acetic acid is added to the pearl bottle, followed by additional acetic acid (200 mL). added. The vessel was capped and placed in a Parr apparatus and hydrogenated at 45 psi for 12 hours. Shake for 2 days under H ₂ atmospheric pressure (100 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by preparative chromatography to give 4.1 g of the title compound (TFA salt). LCMS ES (M + H)) = 181.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.8-11.9 (brs, 1H), 7.83-7.88 (brs, 3H), 5.99 (s, 1H), 3. 77-3.81 (m, 2H), 2.37 (t, 2H), 1.53 (m, 2H), 0.83 (t, 3H).

Intermediate 16
3- (Aminomethyl) -6-cyclopropyl-4-methyl-2 (1H) -pyridinone

Process 1
1-cyclopropyl-1,3-butanedione suspended in potassium tert-butoxide (5.60 g, 49.5 mmol) in a stirred solution of THF (100 mL) followed by cyclopropyl methyl ketone (3.27 mL, 33 mmol) And a mixture of ethyl acetate (9.69 mL, 99 mmol) were suspended in an addition funnel at 30 ° C. in 30 mL of THF over 25 minutes. The contents were heated and stirred at 60 ° C. After 3 hours, the contents were removed from the heat and stirred while cooling to room temperature. The reaction mixture was carefully diluted with 30 mL of 2N HCl and stirred for 10 minutes. The mixture was extracted with diethyl ether (3 × 50 mL) and the combined organic layers were washed with brine (1 × 50 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated under vacuum. The crude oil is chromatographed on silica gel (eluent: 0-15% EtOAc in hexanes), separating well and the desired product is 3.9 g of pale yellow oil, purity -75% (residual solvent), Obtained as an overall yield of 70%. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.89-0.96 (m, 2H), 1.09-1.15 (m, 2H), 1.59-1.69 (m, 1H) , 2.04 (s, 3H), 5.63 (s, 1H), 15.5-16.0 (brs, 1H).

Process 2
6-Cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

Suspend 1-cyclopropyl-1,3-butanedione (505 mg, 3.00 mmol) and cyanoacetamide (252 mg, 3.00 mmol) in a stirred solution of ethanol (5 mL) to homogenize the heterogeneous contents (About 75 ° C.). Piperidine (0.395 mL, 4.00 mmol) was then added and the mixture was stirred for 30 minutes while warming to reflux. The reaction mixture was cooled to room temperature where precipitation occurred. The solid precipitate was filtered and set aside. The filtrate was concentrated in vacuo and the oily residue was treated with a minimum amount of EtOAc and then with 10 mL of hexane to give a second portion of the solid. The solid product crops were combined, suspended in water (7 mL), stirred vigorously and vacuum filtered to give an almost white solid, 380 mg (73%). LCMS ES (M + H) = 175.1. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.01-1.09 (m, 2H), 1.28 (dd, J = 8.59, 2.27 Hz, 2H), 1.95-2. 01 (m, 1H), 2.43 (s, 3H), 5.82 (s, 1H).

Process 3
1,1-dimethylethyl [(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] carbamate

6-Cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.35 g, 2.01 mmol) was added to methanol (20 mL) and the stirred contents were added at −10 ° C. Chilled. Then di-tert-butyloxycarbonyl (0.933 mL, 4.02 mmol) was added and the suspension was stirred for 15 minutes. Next, NiCl ₂ -6H ₂ O (0.055 g, 0.201 mmol) was added as a solid and stirred for 5 minutes.
Next, NaBH ₄ (0.532 g, 14.06 mmol) was added in 6 portions each 5 minutes apart. After the addition was complete (about 30 minutes), the ice bath was removed and the contents were stirred overnight while warming to room temperature. The reaction mixture was returned to −10 ° C., followed by addition of NaBH ₄ (0.532 g, 14.06 mmol) in three more portions. The ice bath was removed and the mixture was stirred at room temperature for 1 hour.
The contents were quenched by the addition of diethylethyleneamine (0.218 mL, 2.01 mmol) and stirred at room temperature for 45 minutes. Volatiles were removed in vacuo and the residue was suspended in EtOAc and saturated NaHCO ₃ . The organic layer was washed with additional NaHCO ₃ . The layers were separated and the organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: 10% methanol in dichloromethane). The recovered product was dried under high vacuum for 1 hour, then treated with ether and filtered. After drying in a vacuum oven at 45 ° C. for 2 hours, 0.28 g (50%) of product was recovered. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.73-0.80 (m, 2H), 0.88-0.96 (m, 2H), 1.36 (s, 9H), 70-1.82 (m, 1H), 2.11 (s, 3H), 3.95 (d, J = 5.31 Hz, 2H), 5.66 (s, 1H), 6.51 (t, J = 4.80 Hz, 1H), 11.50 (br.s., 1H).

Process 4
3- (Aminomethyl) -6-cyclopropyl-4-methyl-2 (1H) -pyridinone hydrochloride 1,1-dimethylethyl [(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro -3-pyridinyl) methyl] carbamate (0.28 g, 1.006 mmol) was added to EtOAc (9 mL) and methanol (1.0 mL). The suspension was stirred at room temperature for 5 minutes, followed by the addition of 4M HCl in dioxane (5.03 mL, 20.12 mmol) and the contents stirred overnight at room temperature. The volatile material was then removed under vacuum to give a solid. The solid was triturated with ether, filtered and dried in a vacuum oven at 45 ° C. for 4 hours. 0.22 g of the title compound was recovered (yield 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.78-0.86 (m, 2H), 0.95-1.03 (m, 2H), 1.83 (tt, J = 8.46) , 5.05 Hz, 1H), 2.16-2.22 (m, 3H), 3.75 (q, J = 5.47 Hz, 2H), 5.79 (s, 1H), 8.02 (br S., 3H), 11.92 (br.s., 1H).

Example 1
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide

6-chloro-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (0.12 g, 0.501 mmol), 1-hydroxy-7-azabenzotriazole (0 .102 g, 0.751 mmol), EDC (0.144 g, 0.751 mmol), and 3- (aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (0.123 g, 0.651 mmol) in dimethyl Sulfoxide (3.0 mL) was dissolved and stirred at room temperature. Next, N-methylmorpholine (0.220 mL, 2.003 mmol) was added to the stirred contents at once using a syringe. After stirring at room temperature overnight, the reaction mixture was slowly added to water (75 mL) and stirred for 10 minutes. After standing at room temperature for 10 minutes, the contents were filtered to give a tan solid which was washed with water and then with cold 50% aqueous EtOH. The contents were filtered and air dried for 10 minutes, then dried under vacuum for 1 hour. The recovered solid was then further dried in a vacuum oven at 45 ° C. for 4 hours. 0.105 g (55%) of the title compound was recovered. LCMS ES (M + H) = 373.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.49 (d, J = 6.82 Hz, 6H), 2.13 (s, 3H), 2.20 (s, 3H), 4.35 ( d, J = 4.80 Hz, 2H), 5.07-5.20 (m, 1H), 5.89 (s, 1H), 7.66 (s, 1H), 8.39 (s, 1H) , 8.91 (t, J = 4.80 Hz, 1H), 11.55 (s, 1H).

Example 2
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

6-Chloro-3-methyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (486.6 mg, 1.92 mmol), 3- (aminomethyl)- 4,6-Dimethyl-2 (1H) -pyridinone. Using HCl (489 mg, 2.59 mmol) and 1-hydroxy-7-azabenzotriazole (392 mg, 2.88 mmol), N-methylmorpholine (0.84 mL, 7.67 mmol), EDC (552 mg, 2.88 mmol) The title compound was prepared as described in Example 17.
10 mL of additional DMSO was added to the reaction mixture to facilitate stirring and then 10% K ₂ CO ₃ was used instead of 50% aqueous NaOH during the study. LCMS ES (M + H) = 388.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.44 (d, 6H), 2.12 (s, 3H), 2.22 (s, 3H), 2.40 (s, 3H), 4 .34 (d, J = 0.05 Hz, 2H), 5.05 (quin, J = 6.63 Hz, 1H), 5.88 (s, 1H), 7.16 (s, 1H), 8.78 (T, J = 4.93 Hz, 1H), 11.53 (br.s., 1H).

Example 3
6-Chloro-1- (1,1-dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide

A solution of 6-chloro-1- (1,1-dimethylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (320 mg, 1.195 mmol) in DMSO (7 mL) 3- (aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (338 mg, 1.793 mmol), N-methylmorpholine (0.526 mL, 4.78 mmol), 1-hydroxy-7-aza Benzotriazole (325 mg, 2.391 mmol) and EDC (458 mg, 2.391 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was quenched with water (20 mL) and stirred for 10 minutes. The precipitate was collected by filtration and further dried under high vacuum to give the product as a solid 450 mg (94%). LCMS ES (M + H) = 402.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.71 (s, 9H), 2.12 (s, 3H), 2.22 (s, 3H), 2.37 (s, 3H), 4 .33 (d, J = 4.80 Hz, 2H), 5.88 (s, 1H), 7.09-7.21 (m, 1H), 8.77 (t, J = 4.93 Hz, 1H) , 11.53 (s, 1H).

Example 4
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyloxy) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (0.15 g, 0.401 mmol), 4-pyridine ol (0.057 g, 0.602 mmol), cesium carbonate (0.261 g, 0.802 mmol), and 1- (2-pyridinyl)- 2-propanone (10.85 mg, 0.080 mmol) was dissolved sequentially in DMSO (4.0 mL). Next, copper (I) bromide (5.76 mg, 0.040 mmol) was added and the suspension was stirred for 1 minute under nitrogen (degassed). The sealed reaction mixture was heated (heating block) at 110 ° C. and stirred for 20 hours, then cooled to room temperature overnight. The reaction mixture was diluted with EtOAc (25 mL) and water. The contents were stirred vigorously and then filtered through celite and the filter pad was washed with 20% THF / EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated under vacuum to a dark residue that was dried overnight under high vacuum. The crude product was purified by silica gel chromatography (eluent: 5-95% dichloromethane / chloroform gradient containing 2M ammonia in methanol). The recovered product was washed with MTBE, filtered and dried in a vacuum oven at 45 ° C. for 5 hours. 0.075 g (42%) of the final product was recovered. LCMS ES (M + H) = 433.2. ^{1 H NMR (400MHz, DMSO-} d 6) δppm 1 H NMR (400MHz, DMSO-d 6) δ ppm 1.52 (d, J = 6.57Hz, 6H), 2.13 (s, 3H), 2 .22 (s, 3H), 4.41 (d, J = 0.05 Hz, 2H), 5.18-5.30 (m, 1H), 5.91 (s, 1H), 6.30-6 .40 (m, 2H), 7.91 (s, 1H), 8.41 (s, 1H), 8.57-8.65 (m, 2H), 8.92 (t, J = 4.93 Hz) , 1H), 11.58 (s, 1H).

Example 5
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-propen-1-ylamino) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (0.25 g, 0.669 mmol) was suspended in ethanol (4 mL) followed by addition of allylamine (0.753 mL, 10.03 mmol). The sealed contents were heated at 140 ° C. for about 60 hours (heating block) and then cooled to room temperature. The reaction mixture was diluted with water (100 mL) and then filtered. The collected solid was washed with additional water and then dried in a vacuum oven at 45 ° C. for 18 hours. The final product was isolated as an off-white solid, 0.225 g (83%). LCMS ES (M + H) = 394.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (d, J = 6.82 Hz, 6H), 2.12 (s, 3H), 2.21 (s, 3H), 4.00 ( t, J = 5.43 Hz, 2H), 4.32 (d, J = 0.05 Hz, 2H), 4.94 (quin, J = 6.69 Hz, 1H), 5.09 (dd, J = 10 .36, 1.77 Hz, 1H), 5.18-5.29 (m, 1H), 5.85-6.01 (m, 2H), 6.68 (s, 1H), 7.37 (t , J = 5.56 Hz, 1H), 7.84 (s, 1H), 8.45 (t, J = 0.05 Hz, 1H), 11.55 (br.s., 1H).

Example 6
6-amino-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide

10% Pd / C (0.200 g, 0.188 mmol) and N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) A mixture of -6- (2-propen-1-ylamino) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide (0.200 g, 0.507 mmol) was suspended in ethanol (10 mL) and stirred. did. Then methanesulfonic acid (0.033 mL, 0.507 mmol) was added and the stirred contents were heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was diluted with DCM and filtered through celite. The filter pad was washed with 10% MeOH / DCM. The filtrate was pre-adsorbed onto silica gel and the crude product was purified by silica gel chromatography (dry loaded, eluent: 5-80% gradient of dichloromethane / chloroform containing 10% 2M ammonia in methanol). Purified. The recovered product was dried in a vacuum oven at 45 ° C. overnight. 0.065 g (36%) of the final product was recovered. LCMS ES (M + H) = 355.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.40 (d, J = 6.82 Hz, 6H), 2.12 (s, 3H), 2.21 (s, 3H), 4.31 ( d, J = 5.05 Hz, 2H), 4.85-5.00 (m, 1H), 5.89 (s, 1H), 6.49-6.68 (m, 3H), 7.85 ( s, 1H), 8.46 (t, J = 0.05 Hz, 1H), 11.54 (br.s., 1H).

Example 7
6-Cyclopropyl-1- (1-methylethyl) -N-[(4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinyl) methyl] -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide

6-Cyclopropyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (167 mg, 0.680 mmol), 3- (aminomethyl) -4-methyl-6 -Propyl-2 (1H) -pyridinone trifluoroacetate (200 mg, 0.680 mmol), HOAT (139 mg, 1.019 mmol), EDC (195 mg, 1.019 mmol), and N-methylmorpholine (0.299 mL, 2 .72 mmol) was dissolved in DMF (6 mL) and stirred at 40 ° C. for 24 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to an orange oil. The residue was dissolved in DMSO and purified by reverse phase HPLC (mobile phase: 40-60% ACN in H ₂ O, 0.1% TFA). The isolated product was dried in a vacuum oven overnight to give 0.113 g (32%) of the TFA salt of the title compound as a white solid. LCMS ES (M + H) = 408.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.80-0.98 (m, 3H), 1.06 (d, J = 7.07 Hz, 4H), 1.46 (d, J = 6 .82 Hz, 6H), 1.52-1.67 (m, 2H), 2.17-2.31 (m, 4H), 2.37 (t, J = 7.58 Hz, 2H), 4.36 (D, J = 4.80 Hz, 2H), 5.02-5.27 (m, 1H), 5.91 (s, 1H), 7.43 (s, 1H), 8.21 (s, 1H) ), 8.62-8.87 (m, 1H), 11.54 (br.s., 1H).

Example 8
6-cyclopropyl-1- (1-methylethyl) -N-{[6-methyl-4- (1-methylethyl) -2-oxo-1,2-dihydro-3-pyridinyl] methyl} -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

6-Cyclopropyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (250 mg, 1.019 mmol), 3- (aminomethyl) -6-methyl-4 -(1-Methylethyl) -2 (1H) -pyridinone TFA (300 mg, 1.019 mmol), HOAT (208 mg, 1.529 mmol), EDC (293 mg, 1.529 mmol), N-methylmorpholine (0.448 mL) 4.08 mmol), and DMF (6 mL), the title compound was prepared in the same manner as described in Example 7, where the reaction time was 48 hours. After basic extraction (to remove residual starting material), 30 mg (7%) of the final product was recovered as a white solid. LCMS ES (M + H) = 408.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.95-1.16 (m, 10H), 1.38-1.54 (m, 6H), 2.16 (s 3H), 2.19 -2.30 (m, 1H), 3.12-3.29 (m, 1H), 4.29-4.48 (m, 2H), 5.03-5.21 (m, 1H), 6 .03 (s, 1H), 7.39 (s, 1H), 8.21 (s, 1H), 8.63-8.81 (m, 1H), 11.56 (s, 1H).

Example 9
1- (1-Methylethyl) -N-[(4-Methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinyl) methyl] -6- (4-pyridinyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (192 mg, 0.680 mmol), 3- (aminomethyl) -4- Methyl-6-propyl-2 (1H) -pyridinone TFA (200 mg, 0.680 mmol), HOAT (139 mg, 1.019 mmol), EDC (195 mg, 1.019 mmol), and N-methylmorpholine (0.299 mL, 2.72 mmol) was added sequentially to DMF (6 mL) and the mixture was stirred at 40 ° C. overnight. The reaction mixture was then filtered. The collected solid was washed with ethanol and dried to give the final product as a white solid, 0.160 g (53%). LCMS ES (M + H) = 445.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.88 (t, 3H), 1.46 to 1.65 (m, 8H), 2.24 (s, 3H), 2.38 (t, J = 7.58 Hz, 2H), 4.43 (d, J = 4.80 Hz, 2H), 5.37 (s, 1H), 5.93 (s, 1H), 8.23 (d, J = 5.81 Hz, 2H), 8.30 (s, 1H), 8.45 (s, 1H), 8.78 (d, J = 5.31 Hz, 2H), 9.00 (br.s., 1H) ), 11.56 (s, 1H).

Example 10
N-[(6-Ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (403 mg, 1.427 mmol), 3- (aminomethyl) -6- Ethyl-4-methyl-2 (1H) -pyridinone TFA (400 mg, 1.427 mmol), HOAT (291 mg, 2.141 mmol), EDC (1094 mg, 5.71 mmol), N-methylmorpholine (0.628 mL, 5 .71 mmol), and DMF (6 mL), the title compound was prepared in the same manner as described in Example 9. The final product was recovered as a white solid, 232 mg (38%). LCMS ES (M + H) = 432.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm
1.14 (t, 3H), 1.56 (d, J = 6.57 Hz, 6H), 2.25 (s, 3H), 2.42 (q, J = 7.41 Hz, 2H), 4. 43 (d, J = 4.55 Hz, 2H), 5.29-5.45 (m, 1H), 5.93 (s, 1H), 8.22 (d, J = 6.06 Hz, 2H), 8.30 (s, 1H), 8.45 (s, 1H), 8.78 (d, J = 5.81 Hz, 2H), 9.01 (t, J = 4.55 Hz, 1H), 11. 58 (s, 1H).

Example 11
1- (1-Methylethyl) -N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl) methyl] -6- (4-pyridinyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (150 mg, 0.531 mmol), 3- (aminomethyl) -6- Methyl-4-propyl-2 (1H) -pyridinone (115 mg, 0.531 mmol), EDC (122 mg, 0.638 mmol), HOAt (72.3 mg, 0.531 mmol), and N-methylmorpholine (0.233 mL, 2.12 mmol) was suspended in DMF (5 mL) and stirred overnight at room temperature. Water was added to the reaction mixture and the contents were filtered. The filter cake was washed with additional water (2x). The crude solid was purified by reverse phase HPLC (mobile phase: 10-30% ACN in H ₂ O, 0.1% TFA). The isolated solid was then neutralized with saturated NaHCO ₃ and washed with EtOAc (5 × 15 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as an off-white solid, 0.060 g (24%). LCMS ES (M + H) = 445.3. ¹ H
NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.84-0.92 (m, 3H), 1.47-1.54 (m, 2H), 1.57 (d, J = 6.82 Hz, 6H ), 2.14 (s, 3H), 2.48-2.52 (m, 2H), 4.42-4.49 (m, 2H), 5.33-5.43 (m, 1H), 5.90-5.96 (m, 1H), 8.28-8.37 (m, 3H), 8.44-8.48 (m, 1H), 8.82-8.87 (m, 2H) ), 8.99-9.04 (m, 1H), 11.58 (s, 1H).

Example 12
1- (1-Methylethyl) -N-{[6-Methyl-4- (1-methylethyl) -2-oxo-1,2-dihydro-3-pyridinyl] methyl} -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (288 mg, 1.019 mmol), 3- (aminomethyl) -6- Methyl-4- (1-methylethyl) -2 (1H) -pyridinone TFA (300 mg, 1.019 mmol), HOAT (208 mg, 1.529 mmol), EDC (782 mg, 4.08 mmol), and N-methylmorpholine (0.448 mL, 4.08 mmol) in DMF (6 mL) was stirred at 40 ° C. overnight. After cooling to room temperature, the reaction mixture was poured into H ₂ O (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAC (2 × 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in DMSO, reversed-phase _{(H 2} O in 15~40% ACN, 0.1% TFA) and purified by. The product fraction was poured into sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (123 mg, 27% yield). LCMS ES (M + H) = 445.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.10 (m, 6H), 1.56 (m, 6H), 2.17 (s, 3H), 3.17-3.28 (m, 1H), 4.45-4.56 (m, 2H), 5.29-5.43 (m, 1H), 5.99-6.12 (m, 1H), 8.16-8.23 ( m, 2H), 8.24-8.29 (m, 1H), 8.40-8.46 (m, 1H), 8.71-8.82 (m, 2H), 8.96-9. 04 (m, 1H), 11.53-11.63 (m, 1H).

Example 13
6-Cyclopropyl-1- (1-methylethyl) -N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl) methyl] -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide

The title compound is described in Example 11 from 1- (1-methylethyl) -6- (cyclopropyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (150 mg, 0.612 mmol). Prepared in the same manner as The product was recovered as a white solid, 0.043 g (16%). LCMS ES (M + H) = 408.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.89 (t, J = 7.20 Hz, 3H), 1.06 (d, J = 2.78 Hz, 3H), 1.08 (br.s) , 1H), 1.47 (d, J = 6.57 Hz, 8H), 1.49-1.57 (m, 2H), 2.14 (s, 3H), 2.19-2.30 ( m, 1H), 4.38 (d, J = 4.80 Hz, 2H), 5.03-5.18 (m, 1H), 5.92 (s, 1H), 7.40 (s, 1H) , 8.21 (s, 1H), 8.69-8.76 (m, 1H), 11.55 (s, 1H).

Example 14
1- (1-Methylethyl) -N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl) methyl] -6- (4-pyridinyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (150 mg, 0.531 mmol) and 3- (aminomethyl) -6- The title compound was prepared in the same manner as described in Example 11 from methyl-4-phenyl-2 (1H) -pyridinone (133 mg, 0.531 mmol). The product was recovered as a white solid, 0.041 g (15%). LCMS ES (M + H) = 479.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.57 (d, J = 6.82 Hz, 6H) 2.23 (s, 3H) 4.23-4.27 (m, 2H) 5.33 -5.42 (m, 1H) 6.02-6.04 (m, 1H) 7.35-7.42 (m, 1H) 7.43 (s, 4H) 8.23-8.26 (m , 1H) 8.34-8.39 (m, 2H) 8.41-8.42 (m, 1H) 8.84-8.88 (m, 2H) 8.91-8.96 (m, 1H) ) 11.91 (s, 1H).

Example 15
N-[(4-Cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (169 mg, 0.6 mmol), 3- ( Aminomethyl) -4-cyclohexyl-6-methyl-2 (1H) -pyridinone trifluoroacetate (221 mg, 0.660 mmol), EDC (150 mg, 0.780 mmol), HOAT (106 mg, 0.780 mmol), and N -A mixture of methylmorpholine (0.264 mL, 2.400 mmol) was stirred at room temperature for 6 days. Water (15 mL) was added to the slurry and it was stirred for 1 hour. The precipitate was then collected by vacuum filtration, rinsed with EtOH (4 mL), and the solid was dried in a vacuum oven overnight to give the title compound as an off-white solid (137 mg, 45%). LCMS ES (M + H) = 485.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.09-1.44 (m, 5H), 1.56 (d, J = 6.57 Hz, 6H), 1.55-1.72 (m , 5H), 2.15 (s, 3H), 2.80-2.92 (m, 1H), 4.53 (d, J = 4.55 Hz, 2H), 5.36 (spt, J = 6 .53 Hz, 1H), 6.03 (s, 1H), 8.18-8.23 (m, 2H), 8.26 (s, 1H), 8.45 (s, 1H), 8.75- 8.82 (m, 2H), 9.01 (t, J = 4.55 Hz, 1H), 11.59 (s, 1H).

Example 16
N-[(4-Cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6-cyclopropyl-1- (1-methylethyl) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide

6-Cyclopropyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (147 mg, 0.60 mmol), 3- (aminomethyl) -4-cyclohexyl-6 -Methyl-2 (1H) -pyridinone trifluoroacetate (221 mg, 0.660 mmol), EDC (150 mg, 0.780 mmol), HOAT (106 mg, 0.780 mmol), N-methylmorpholine (0.264 mL, 2. (400 mmol) and DMF (3 mL), the title compound was prepared in the same manner as described in Example 15, where the stirring time was 3 days and the final product was not treated with EtOH. The final product was recovered 193 mg (68%). LCMS ES (M + H) = 448.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.01-1.11 (m, 4H), 1.15-1.43 (m, 5H), 1.47 (d, J = 6.57 Hz) , 6H), 1.55-1.76 (m, 5H), 2.15 (s, 3H), 2.19-2.28 (m, 1H), 2.83 (t, J = 11.12 Hz) , 1H), 4.45 (d, J = 0.05 Hz, 2H), 5.12 (spt, J = 6.69 Hz, 1H), 6.02 (s, 1H), 7.37 (s, 1H) ), 8.21 (s, 1H), 8.74 (t, J = 4.80 Hz, 1H), 11.56 (s, 1H).

Example 17
6-Cyclopropyl-1- (1-methylethyl) -N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl) methyl] -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (cyclopropyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (150 mg, 0.612 mmol) and 3- (aminomethyl) -6-methyl The title compound was prepared in the same manner as described in Example 11 from -4-phenyl-2 (1H) -pyridinone (153 mg, 0.612 mmol). The product was recovered as a white solid, 0.067 g (24%). LCMS ES (M + H) = 442.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.04-1.11 (m, 3H), 1.47 (d, J = 6.57 Hz, 5H), 2.22 (s, 3H), 2.4-2.29 (m, 1H), 3.17 (d, J = 5.31 Hz, 2H), 4.07-4.15 (m, 1H), 4.19 (d, J = 4 .29 Hz, 2H), 5.06-5.18 (m, 1H), 6.01 (s, 1H), 7.36 (s, 1H), 7.38-7.49 (m, 5H), 8.18 (s, 1H), 8.70 (s, 1H), 11.88 (s, 1H).

Example 18
N-[(4-Cyclopropyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (100 mg, 0.354 mmol), 3- (aminomethyl) -4- Cyclopropyl-6-methyl-2 (1H) -pyridinone (104 mg, 0.354 mmol), EDC (81 mg, 0.425 mmol), HOAt (48 mg, 0.354 mmol), and N-methylmorpholine (0.156 mL, 1 .42 mmol) was suspended in DMF (5 mL) and stirred overnight at room temperature. The contents were filtered, washed with ethanol and then concentrated in vacuo. The crude solid by reverse phase HPLC (mobile phase: _{H 2} O in 20~40%, ACN, 0.1% TFA ) and purified by. The isolated solid was then neutralized with saturated NaHCO ₃ and washed with EtOAc (3 ×). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as an off-white solid, 0.042 g (26%). LCMS ES (M + H) = 443.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.71-0.78 (m, 2H), 0.94 (dd, J = 8.34, 2.27 Hz, 2H), 1.57 (d , J = 6.57 Hz, 6H), 2.12 (s, 3H), 2.13-2.18 (m, 1H), 4.62 (d, J = 4.80 Hz, 2H), 5.38. (S, 1H), 5.54 (s, 1H), 8.37 (s, 1H), 8.44-8.54 (m, 3H), 8.91 (d, J = 6.06 Hz, 2H ), 9.04 (s, 1H), 11.51 (br.s., 1H).

Example 19
6-cyclopropyl-N-[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

To a solution of 4 mL of DMSO was added 6-cyclopropyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (0.11 g, 0.448 mmol), 3- ( Aminomethyl) -6-cyclopropyl-4-methyl-2 (1H) -pyridinone hydrochloride (0.106 g, 0.493 mmol), 1-hydroxy-7-azabenzotriazole (0.073 g, 0.538 mmol), EDC (0.103 g, 0.538 mmol) and then N-methylmorpholine (0.197 mL, 1.79 mmol) were added sequentially using a syringe. After stirring overnight at room temperature, the suspension was diluted with 50 mL of water and stirred for 15 minutes. After 15 minutes at room temperature, the reaction mixture was filtered and the collected solid was washed with additional water. Next, it was dried in a vacuum oven at 45 ° C. for 4 hours. 0.165 g (89%) of product was obtained. LCMS ES (M + H) = 406.5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.76-0.82 (m, 2H), 0.91-0.98 (m, 2H), 1.03-1.12 (m, 4H) ), 1.46 (d, J = 6.82 Hz, 6H), 1.74-1.84 (m, 1H), 2.19 (s, 3H), 2.21-2.31 (m, 1H) ), 4.34 (d, J = 0.05 Hz, 2H), 5.05-5.18 (m, 1H), 5.73 (s, 1H), 7.42 (s, 1H), 8. 21 (s, 1H), 8.72 (t, J = 4.93 Hz, 1H), 11.61 (br.s., 1H).

Example 20
N-[(5-Fluoro-4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (169 mg, 0.60 mmol), 3- ( Aminomethyl) -5-fluoro-4,6-dimethyl-2 (1H) -pyridinone hydrochloride (136 mg, 0.660 mmol), EDC (150 mg, 0.780 mmol), HOAT (106 mg, 0.780 mmol), and N -A mixture of methylmorpholine (0.264 mL, 2.400 mmol) was stirred at room temperature for 3 days. Water (15 mL) was added to the slurry and it was stirred for 1 hour. The precipitate was then collected by vacuum filtration, rinsed with EtOH (4 mL), and the solid was dried in a vacuum oven overnight to give 220 mg (76%) of the title compound. LCMS ES (M + H) = 435.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.56 (d, 7H), 2.18 (d, J = 2.78 Hz, 3H), 2.25 (d, J = 2.02 Hz, 3H ), 4.45 (d, J = 4.80 Hz, 2H), 5.37 (spt, J = 6.65 Hz, 1H), 8.19-8.25 (m, 2H), 8.29 (s). , 1H), 8.44 (s, 1H), 8.74-8.81 (m, 2H), 9.07 (t, J = 4.80 Hz, 1H), 11.66 (br.s., 1H).

Example 21
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (ethylamino) -1- (1-methylethyl) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide

In a 10 mL microwave vial with stir bar, septum cap and nitrogen inlet, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl]- 1- (1-Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide (23 mg, 0.062 mmol) and ethanol (1 mL) were added.
Next, ethylamine (0.100 mL, 1.230 mmol) was added to the stirred suspension at once using a syringe. The sealed reaction mixture was irradiated (microwave) at 110 ° C. for 40 minutes, followed by addition of 0.1 mL ethylamine and further irradiation at 130 ° C. for 7 hours. After cooling to room temperature, about 50% of the volatile material was removed by a stream of nitrogen. The reaction mixture was diluted with water (20 mL) and stirred for 10 minutes. The mixture was then filtered and the collected solid was washed with water. The solid was dried in a vacuum oven at 50 ° C. for 18 hours to give 0.17 g (71%) of the title compound. LCMS ES (M + H) = 383.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.17 (t, J = 7.07 Hz, 3H), 1.43 (d, J = 6.57 Hz, 6H), 2.12 (s, 3H ), 2.21 (s, 3H), 3.35-3.39 (m, 2H), 4.31 (d, J = 0.05Hz, 2H), 4.89-5.01 (m, 1H) ), 5.89 (s, 1H), 6.61 (s, 1H), 7.18 (t, J = 5.31 Hz, 1H), 7.83 (s, 1H), 8.44 (t, J = 5.05 Hz, 1H), 11.55 (br.s., 1H).

Example 22
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4- Carboxamide

In a 50 mL round bottom flask with a 3-way inlet, place 10% Pd / C (0.071 g, 0.033 mmol) followed by degassing with N ₂ followed by ₂ mL ethanol. added. The stirred slurry was then added to 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (0.25 g, 0.669 mmol) was added. Additional ethanol (8 mL) and THF (10 mL) were added with slight warming to facilitate dissolution. The stirred contents were cooled (15 minutes), then a H ₂ balloon was attached and stirred overnight at room temperature. Then, the contents were purged with N _2. The mixture was then diluted with 10% MeOH / DCM (20 mL), stirred for 10 minutes and filtered through celite. The filtrate was concentrated under vacuum and the crude solid was triturated with ethanol. After filtration and washing the recovered solid with additional (cold) ethanol, the solid was air dried for 15 minutes and then dried in a vacuum oven at 40 ° C. overnight. The final product was recovered 185 mg (80%). LCMS ES (M + H) = 340.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.50 (d, J = 6.82 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 4.37 ( d, J = 4.80 Hz, 2H), 5.18-5.31 (m, 1H), 5.89 (s, 1H), 7.54 (d, J = 4.80 Hz, 1H), 8. 36 (s, 1H), 8.63 (d, J = 4.55 Hz, 1H), 8.82 (t, J = 4.93 Hz, 1H), 11.56 (s, 1H).

Example 23
6-Cyclopropyl-1- (1-methylethyl) -N-{[6-methyl-2-oxo-4- (trifluoromethyl) -1,2-dihydro-3-pyridinyl] methyl} -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-cyclopropyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (0.12 g, 0.489 mmol), 1-hydroxy-7-azabenzotriazole ( 0.100 g, 0.734 mmol), 3- (aminomethyl) -6-methyl-4- (trifluoromethyl) -2 (1H) -pyridinone (0.154 g, 0.636 mmol, DMSO (3.0 mL), The title compound was prepared from N-methylmorpholine (0.215 mL, 1.957 mmol) and EDC (0.141 g, 0.734 mmol) in the same manner as described in Example 19. The crude solid was purified on silica gel. chromatography (eluting solution gradient 5-100% of _10% 2M NH 3 (MeOH / in DCM) and DCM) The collected product was dried for 5 hours in a vacuum oven. The final product 0.112 g (50%) recovered ^{.LCMS E-S (M + H} ) = 434.3. 1 H NMR (400MHz, DMSO-d 6) δ ppm 1.03-1.12 (m, 4H), 1.47 (d, J = 6.82 Hz, 6H), 2.20-2.33 (m, 4H), 4.34-4.54 (M, 2H), 5.12 (quin, J = 6.63 Hz, 1H), 6.33 (s, 1H), 7.39 (s, 1H), 8.18 (s, 1H), 8. 70 (t, J = 4.04 Hz, 1H), 12.43 (s, 1H).

Example 24
6- (Dimethylamino) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] The title compound was prepared in the same way as described in Example 21 from pyridine-4-carboxamide (23 mg, 0.062 mmol), ethanol (0.7 mL), and dimethylamine (0.461 mL, 0.923 mmol). did. The product was dried in a vacuum oven at 50 ° C. for 5 hours and recovered 0.016 g (67%). LCMS ES (M + H) = 383.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.44 (d, J = 6.57 Hz, 6H), 2.05-2.25 (m, 6H), 3.14 (s, 6H), 4.34 (d, J = 4.80 Hz, 2H), 4.99 (dt, J = 13.39, 6.69 Hz, 1H), 5.89 (s, 1H), 6.94 (s, 1H) ), 7.96 (s, 1H), 8.64 (t, J = 4.93 Hz, 1H), 11.56 (br.s., 1H).

Example 25
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (1-piperidinyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

To a 10 mL reaction vial containing a stir bar, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl)- 1H-pyrazolo [3,4-b] pyridine-4-carboxamide (.060 g, 0.160 mmol), ethanol (1.5 mL), then piperidine (0.318 mL, 3.21 mmol) are added in one portion using a syringe. It was. The contents were covered with a lid, placed on a heat block and heated at 120 ° C. for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water (40 mL), adjusted to pH 6-7 and stirred for 15 minutes. The contents were filtered and washed with water. The product was dried in a vacuum oven at 50 ° C. for 5 hours. 57 mg (82%) of product was obtained. LCMS ES (M + H) = 422.8. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ
ppm 1.43 (d, J = 6.82 Hz, 6H), 1.53-1.67 (m, 6H), 2.12 (s, 3H), 2.20 (s, 3H), 3.61 -3.73 (m, 4H), 4.34 (d, J = 5.05 Hz, 2H), 4.91-5.04 (m, 1H), 5.89 (s, 1H), 7.10 (S, 1H), 7.97 (s, 1H), 8.65 (t, J = 4.93 Hz, 1H), 11.51 (br.s., 1H).

Example 26
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-morpholinyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

Into a 10 mL reaction vial containing the stirrer, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl)- 1H-pyrazolo [3,4-b] pyridine-4-carboxamide (.060 g, 0.160 mmol), ethanol (1.5 mL), then morpholine (0.280 mL, 3.21 mmol) are added in one portion using a syringe. It was. The contents were covered with a lid, placed on a heat block, heated at 120 ° C. for 18 hours, and then heated at 135 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (40 mL), adjusted to pH 6-7 and stirred for 15 minutes. The contents were filtered and washed with water. The product was dried in a vacuum oven at 50 ° C. for 5 hours. 57 mg (79%) of product was obtained. LCMS ES (M + H) = 425.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.44 (d, J = 6.57 Hz, 6H), 2.12 (s, 3H), 2.19 (s, 3H), 3.56- 3.66 (m, 4H), 3.69-3.78 (m, 4H), 4.35 (d, J = 4.80 Hz, 2H), 5.00 (quin, J = 6.63 Hz, 1H) ), 5.89 (s, 1H), 7.13 (s, 1H), 8.03 (s, 1H), 8.65 (t, J = 4.93 Hz, 1H), 11.56 (br. s., 1H).

Example 27
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -6- [6- (4-methyl- 1-piperazinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 10 mL microwave vial, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl)- 1H-pyrazolo [3,4-b] pyridine-4-carboxamide (70 mg, 0.180 mmol), 1-methyl-4- [5- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) -2-pyridinyl] piperazine (71.1 mg, 0.235 mmol), DMSO (2.0 mL) and sodium carbonate (0.271 mL, 0.541 mmol) were added and the mixture was added under nitrogen for 10 minutes. I was degassed. Bis (triphenylphosphine) palladium (II) chloride (10.13 mg, 0.014 mmol) was added and the contents sealed. The mixture was irradiated (microwave) at 140 ° C. for 8 hours. The reaction mixture was then quenched with water (5 mL) and filtered. The crude product was washed with water, dried and then purified by silica gel chromatography _{(eluent: 0~15% (9: 1MeOH /} NH 4 OH) / DCM gradient) of was purified by. The resulting product was treated with MeOH and 1N HCl. The mixture was concentrated under vacuum, dried under high vacuum and 42 mg (36%) was recovered as the HCl salt. LCMS ES (M + H) = 529.0 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.50 (d, 6H), 2.13 (s, 3H), 2.25 (s, 3H) , 2.42 (s, 3H), 2.81 (d, J = 4.55 Hz, 3H), 3.03-3.21 (m, 2H), 3.41 (br.s., 2H), 3.52 (d, J = 11.37 Hz, 2H), 4.39 (d, J = 0.05 Hz, 2H), 4.56 (d, J = 14.40 Hz, 2H), 5.23 (quin , J = 6.63 Hz, 1H), 5.91 (s, 1H), 7.19 (d, J = 9.09 Hz, 1H), 7.68 (s, 1H), 8.50 (dd, J = 9.09, 2.27 Hz, 1H), 8.73 (t, J = 4.93 Hz, 3H), 8.98 (d, J = 2.02 Hz, 3H), 10.97-11.21 (m, 2H)

Example 28
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (1-piperazinyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

In a 10 mL microwave vial with stir bar, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide (.060 g, 0.160 mmol), ethanol (1.5 mL), and 1,1-dimethylethyl 1-piperazinecarboxylate (0.299 g, 1 .605 mmol) was added. The stirred suspension was placed on a heat block, heated at 120 ° C. for 18 hours, and then irradiated (microwave) at 160 ° C. for 2 hours. The contents were cooled to room temperature, diluted in water (40 mL), then adjusted to pH 6-7 and stirred for 15 minutes. The contents were filtered, washed with water and then dried in a high vacuum oven at 50 ° C. for 5 hours. The collected solid (52 mg) was dissolved in CH ₂ Cl ₂ / TFA (3 mL, 2: 1) and stirred at room temperature for 2 hours. Volatiles were removed under vacuum to give a residue which was then dissolved in CH ₂ Cl ₂ and 10% 2M ammonia (in methanol) in chloroform. The crude product was purified by silica gel chromatography (eluent: 10% 2M ammonia in methanol / chloroform and dichloromethane gradient). The isolated solid was dried in a vacuum oven at 45 ° C. for 18 hours to give 38 mg (55% yield) of final product. LCMS ES (M + H) = 423.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.43 (d, J = 6.82 Hz, 6H), 2.08-2.24 (m, 6H), 2.75-2.89 (m , 4H), 3.53-3.64 (m, 4H), 4.34 (d, J = 4.80 Hz, 2H), 4.98 (quin, J = 6.69 Hz, 1H), 5.89. (S, 1H), 7.10 (s, 1H), 8.00 (s, 1H), 8.65 (t, J = 4.93 Hz, 1H), 11.55 (br.s., 1H) .

Example 29
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (3-hydroxy-3-methyl-1-butyn-1-yl) -1- ( 1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 10 mL microwave vial, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (0.15 g, 0.401 mmol), sodium iodide (0.012 g, 0.080 mmol), zinc (5.25 mg, 0.080 mmol), DMSO (2.5 mL) , Triethylamine (0.112 mL, 0.802 mmol), and DBU (0.121 mL, 0.802 mmol) were added sequentially. The suspension was stirred and degassed with nitrogen for 5 minutes to form an emulsion. Then 2-methyl-3-butyn-2-ol (0.194 mL, 2.006 mmol) and Pd (Ph ₃ P) ₄ (0.046 g, 0.040 mmol) were added. The stirred contents were heated at 90 ° C. for 3 hours and then cooled to room temperature. The reaction mixture was poured into water and a solution of 20% THF / EtOAc and stirred. The layers were separated and the organic layer was washed with brine. The organic layer was dried over MgSO ₄ and then filtered through celite and the filter pad was washed with additional EtOAc. The filtrate was concentrated under vacuum and the crude residue was dried overnight with a high vacuum pump. The crude product was purified by silica gel chromatography (eluent: gradient of dichloromethane / chloroform containing 5-80% 10% 2M ammonia in methanol). The collected product was dried in a vacuum oven at 45 ° C. overnight, yielding 0.116 g (67% yield) of final product. LCMS ES (M + H) = 421.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.44-1.55 (m, 12H), 2.13 (s, 3H), 2.20 (s, 3H), 4.35 (d, J = 4.80 Hz, 2H), 5.15-5.26 (m, 1H), 5.70 (s, 1H), 5.89 (s, 1H), 7.65 (s, 1H), 8 .38 (s, 1H), 8.93 (t, J = 4.80 Hz, 1H), 11.55 (s, 1H).

Example 30
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (3-methyl-1H-indazol-5-yl ) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 10 mL microwave vial, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (0.12 g, 0.321 mmol), 1,1-dimethylethyl 3-methyl-5- (4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl) -1H-indazole-1-carboxylate (0.138 g, 0.385 mmol), potassium phosphate (tribasic) (0.204 g, 0.963 mmol), 1,4-dioxane (3 mL ), And water (0.75 mL) were added sequentially. The stirred suspension was degassed with nitrogen for 10 minutes where an emulsion formed. Then PdCl ₂ (dppf) —CH ₂ Cl ₂ adduct (0.039 g, 0.048 mmol) was added and the contents were placed in a heat block and stirred at 105 ° C. overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through celite. The filter pad was washed with 50% THF / EtOAc. Silica gel was added to the combined filtrates and the mixture was concentrated to a solid under vacuum. The contents were purified by silica gel chromatography (dry loaded, eluent: 5-80% gradient of dichloromethane / chloroform containing 10% 2M ammonia in methanol). The isolated solid was dried in a vacuum oven at 45 ° C. overnight to give 0.126 g (81%) of the final product.
LCMS ES (M + H) = 470.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.56 (d, J = 6.57 Hz, 6H), 2.13 (s, 3H), 2.25 (s, 3H), 2.60 ( s, 3H), 4.43 (d, J = 0.05 Hz, 2H), 5.31-5.43 (m, 1H), 5.91 (s, 1H), 7.60 (d, J = 8.84 Hz, 1 H), 8.22 (s, 1 H), 8.29-8.37 (m, 2 H), 8.60 (s, 1 H), 8.97 (t, J = 0.05 Hz, 1H), 11.58 (br.s., 1H), 12.84 (s, 1H).

Example 31
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (phenylethynyl) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide

In a 10 mL microwave vial, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (0.125 g, 0.334 mmol), sodium iodide (10.02 mg, 0.067 mmol) and zinc (4.37 mg, 0.067 mmol), DMSO (2.5 mL ), Triethylamine (0.093 mL, 0.669 mmol) and DBU (0.101 mL, 0.669 mmol) were added sequentially. The stirred suspension was degassed with nitrogen for 5 minutes where an emulsion formed. Next, phenylacetylene (0.110 mL, 1.003 mmol) and Pd (Ph ₃ P) ₄ (0.039 g, 0.033 mmol) were added. The sealed reaction mixture was placed on a heat block and stirred at 90 ° C. for 3 hours, then cooled to room temperature overnight. The contents were poured into water and 20% THF / EtOAc, stirred and the layers were separated. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The filter pad was washed with additional EtOAc. The combined filtrate was concentrated under vacuum to a yellow / orange residue, which was dried with a high vacuum pump. The crude solid was then pre-adsorbed on silica gel and purified by silica gel chromatography (dry loaded, eluent: 5-80% gradient of dichloromethane / chloroform containing 10% 2M ammonia in methanol). did. The isolated product is obtained as a yellow solid, which is then further purified by reverse phase HPLC (mobile phase: 20-90% ACN in H ₂ O, 0.1% TFA, gradient time: 8 minutes). did. The isolated solid was dissolved in 10% MeOH / CH ₂ Cl ₂ and treated with 0.6 g of Silicyl carbonate resin for 30 minutes. The contents were filtered through celite and the filter pad was washed with additional 10% MeOH / CH ₂ Cl ₂ . The combined filtrate was concentrated under vacuum to give a solid that was dried in a vacuum oven for 18 hours. 0.045 g (30%) of the final product was recovered. LCMS ES (M + H) = 440.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.51 (d, J = 6.82 Hz, 6H), 2.13 (s, 3H), 2.21 (s, 3H), 4.37 ( d, J = 4.80 Hz, 2H), 5.18-5.33 (m, 1H), 5.90 (s, 1H), 7.45-7.56 (m, 3H), 7.64- 7.73 (m, 2H), 7.86 (s, 1H), 8.42 (s, 1H), 8.92 (t, J = 4.80 Hz, 1H), 11.55 (br.s. , 1H).

Example 32
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-phenylethyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide

To a suspension of palladium on carbon (0.063 g, 0.059 mmol) in ethanol (1 mL) under nitrogen, N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) Methyl] -1- (1-methylethyl) -6- (4-pyridinylethynyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide (0.13 g, 0.295 mmol), then Ethanol (5 mL) and tetrahydrofuran (THF) (1.5 mL) were added. The suspension was stirred overnight under an atmosphere of hydrogen (about 1 atm, balloon). The reaction mixture was then purged with nitrogen and diluted with 10% MeOH / DCM. Celite was added and the contents were stirred for 15 minutes, then filtered through Celite (analytical grade) and washed with 10% MeOH / DCM. The filtrate was concentrated in vacuo and purified by silica gel chromatography (eluent: gradient of dichloromethane / chloroform containing 5-95%, 10% 2M ammonia in methanol). The collected solid was dried in a vacuum oven at 45 ° C. for 18 hours. The final product was recovered 0.112 g (84%). LCMS ES (M + H) = 445.3. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, J = 6.57 Hz, 6H), 2.13 (s, 3H), 2.21 (s, 3H), 3.08-3 .18 (m, 2H), 3.22-3.29 (m, 2H), 4.36 (d, J = 0.05 Hz, 2H), 5.18 (quin, J = 6.69 Hz, 1H) 5.90 (s, 1H), 7.28 (d, J = 6.06 Hz, 2H), 7.53 (s, 1H), 8.26 (s, 1H), 8.38-8.47. (M, 2H), 8.72 (t, J = 5.05 Hz, 1H), 11.56 (s, 1H).

Example 33
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinylethynyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (0.15 g, 0.401 mmol), sodium iodide (0.012 g, 0.080 mmol), zinc (5.25 mg, 0.080 mmol), DMSO (4.0 mL), triethylamine (0.168 mL) , 1.204 mmol), DBU (0.121 mL, 0.802), 4-ethynylpyridine (0.112 g, 0.802 mmol), and Pd (Ph ₃ P) ₄ (0.046 g, 0.040 mmol), The title compound was prepared in the same manner as described in Example 31. The crude product was purified by silica gel chromatography (eluent: 5-100% gradient of DCM and chloroform containing 10% 2M ammonia in methanol). The isolated product was dried in a vacuum oven for 18 hours to give the final product, 0.032 g (18%). LCMS ES (M + H) = 441.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.51 (d, J = 6.57 Hz, 6H), 2.13 (s, 3H), 2.21 (s, 3H), 4.37 ( d, J = 4.80 Hz, 2H), 5.20-5.32 (m, 1H), 5.90 (s, 1H), 7.62-7.69 (m, 2H), 7.93 ( s, 1H), 8.45 (s, 1H), 8.67-8.75 (m, 2H), 8.93 (t, J = 4.80 Hz, 1H), 11.55 (s, 1H) .

Example 34
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (phenylamino) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide

In a 10 mL microwave vial, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (0.100 g, 0.267 mmol), cesium carbonate (0.305 g, 0.936 mmol), 1,4-dioxane (2.5 mL) and aniline (0.049 mL, 0.535 mmol) was added sequentially. The stirred suspension was degassed with nitrogen for 10 minutes. Then BINAP (0.033 g, 0.053 mmol) and palladium (II) acetate (6.01 mg, 0.027 mmol) were added. The sealed mixture was stirred at 105 ° C. overnight. After cooling to room temperature, the contents were poured into EtOAc and filtered through celite. The filter pad was washed with additional 50% THF / EtOAc. The combined filtrate was treated with silica gel and concentrated under vacuum. The crude product was purified by silica gel chromatography (dry loaded, eluent: 5-80% gradient of DCM and chloroform containing 10% 2M ammonia in methanol). The isolated solid was dried in a vacuum oven overnight and 0.061 g (52%) of the final product was recovered. LCMS ES (M + H) = 431.3. ¹ H
NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.50 (d, J = 6.57 Hz, 6H), 2.13 (s, 3H), 2.23 (s, 3H), 4.35 (d, J = 5.05 Hz, 2H), 4.98-5.11 (m, 1H), 5.90 (s, 1H), 6.93-7.00 (m, 2H), 7.34 (t, J = 7.96 Hz, 2H), 7.86 (d, J = 7.58 Hz, 2H), 7.97 (s, 1H), 8.59 (t, J = 0.05 Hz, 1H), 9. 62 (s, 1H), 11.58 (br.s., 1H).

Example 35
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-[(phenylmethyl) amino] -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide

In a 10 mL microwave vial, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (0.100 g, 0.267 mmol), ethanol (2.0 mL), and then benzylamine (0.350 mL, 3.21 mmol) in turn, one at a time using a syringe. added. The sealed contents were irradiated at 140 ° C. for 3 hours. The contents were transferred to a heat block and heated at 135 ° C. for 16 hours and then at 145 ° C. for an additional 12 hours. After cooling to room temperature, the contents were diluted with CH ₂ Cl ₂ and preadsorbed on silica gel. The crude product was purified by silica gel chromatography (dry loaded, eluent: 5-80% gradient of DCM and chloroform containing 10% 2M ammonia in methanol). The isolated solid was triturated with MTBE, filtered and washed with additional MTBE. The collected solid was dried in a vacuum oven at 45 ° C. overnight to give 0.067 g (55%) of the final product. LCMS ES (M + H) = 445.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.38 (d, J = 6.57 Hz, 6H), 2.12 (s, 3H), 2.20 (s, 3H), 4.31 ( d, J = 5.05 Hz, 2H), 4.56 (d, J = 6.06 Hz, 2H), 4.92 (quin, J = 6.69 Hz, 1H), 5.88 (s, 1H), 6.69 (s, 1H), 7.18-7.25 (m, 1H), 7.26-7.35 (m, 2H), 7.35-7.43 (m, 2H), 7. 77 (t, J = 5.94 Hz, 1H), 7.83 (s, 1H), 8.47 (t, J = 0.05 Hz, 1H), 11.55 (br.s., 1H).

Example 36
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6-methyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide

  In a 25 mL sealable tube, 6-methyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (60 mg, 0.27 mmol) and 3- (aminomethyl) ) -4,6-dimethyl-2 (1H) -pyridinone. HCl (62 mg, 0.33 mmol) was combined with DMSO (3 mL) under nitrogen. 1-Hydroxy-7-azabenzotriazole (56 mg, 0.41 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. N-methylmorpholine (0.11 mL, 0.96 mmol) and EDC (79 mg, 0.41 mmol) were added, the vessel was sealed and the light brown mixture was stirred at room temperature for 2 days. Then 2 mL of water was added and the mixture was stirred for 10 minutes. The precipitated solid was sonicated and placed at room temperature for 10 minutes. The contents were filtered, washed with water and dried to give the title compound (68 mg, 68%) as a pale pink solid. LCMS ES (M + H) = 354.3.1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 8.69 (t, J = 4.80 Hz, 1H), 8.26 (S, 1H), 7.46 (s, 1H), 5.89 (s, 1H), 5.20 (quin, J = 6.69 Hz, 1H), 4.36 (d, J = 5.05 Hz) , 2H), 2.63 (s, 3H), 2.21 (s, 3H), 2.13 (s, 3H), 1.48 (d, J = 6.57 Hz, 6H).

Example 37
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1,6-bis (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine -4-Carboxamide

The title compound was described in Example 52 using 1,6-bis (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (70 mg, 0.28 mmol). Prepared in the same manner as the method to give an off-white solid (95 mg, 86%). LCMS ES (M + H) = 382.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.56 (br.s., 1H, 8.76 (t, J = 4.93 Hz, 1H), 8.26 (s, 1H), 7. 50 (s, 1H), 5.90 (s, 1H), 5.15-5.25 (m, 1H), 4.37 (d, J = 0.05 Hz, 2H), 3.13-3. 23 (m, 1H), 2.22 (s, 3H), 2.13 (s, 3H), 1.50 (d, J = 6.57 Hz, 6H), 1.32 (d, J = 6. 82 Hz, 6H).

Example 38
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3,4-b] Pyridine-4-carboxamide

In a 25 mL sealable tube, 1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (70 mg, 0.25 mmol) and 3- (aminomethyl) ) -4,6-dimethyl-2 (1H) -pyridinone. HCl (56.3 mg, 0.3 mmol) was combined with DMSO (3 mL) under nitrogen. 1-Hydroxy-7-azabenzotriazole (51 mg, 0.37 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. N-methylmorpholine (0.1 mL, 0.87 mmol) and EDC (72 mg, 0.37 mmol) were added, the vessel was sealed and the bright yellow mixture was stirred at room temperature for 2 days. Next, 2 mL of water was added and the contents were stirred for 10 minutes. The precipitated solid was sonicated and placed at room temperature for 10 minutes. The reaction contents were filtered and washed with water. The solid was treated with 2 mL EtOH, sonicated, heated and then cooled to room temperature. The contents were filtered, washed with water and dried to give the title compound (74 mg, 70%) as a white solid. LCMS ES (M + H) = 416.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.58 (s, 1H), 8.98 (t, J = 4.80 Hz, 1H), 8.38 (s, 1H), 8.25− 8.30 (m, 2H), 8.17 (s, 1H), 7.49-7.59 (m, 3H), 5.91 (s, 1H), 5.30-5.38 (m, 1H), 4.42 (d, J = 4.80 Hz, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (d, J = 6.57 Hz, 6H) .

Example 39
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (4-fluorophenyl) -1- (1-methylethyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (90 mg, 0.24 mmol), (4-fluorophenyl) boronic acid (33.7 mg, 0.24 mmol) in 1,4-dioxane (3 mL) under nitrogen. To mix. PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (19.7 mg, 0.024 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium carbonate (77 mg, 0.72 mmol) was added, the vessel was sealed and the mixture was heated at 85 ° C. for 2 hours and then at 100 ° C. overnight. An additional 2 equivalents of boronic acid and 0.2 equivalents of PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct were added. The contents were heated at 120 ° C. for 4 hours, then first irradiated at 160 ° C. for 90 minutes (microwave) and then irradiated at 190 ° C. for 2 hours. After cooling to room temperature, the solid was filtered, washed with DMSO and the filtrate was evaporated. The crude product was first purified by reverse phase HPLC (C18, 5% to 80% CH ₃ CN in water containing 0.1% TFA, gradient for 18 minutes), then silica gel chromatography (eluent: 0 to 90:10). It was purified by a gradient of _{DCM / MeOH / NH 4 OH)} . The collected solid was dried to give the title compound (13 mg, 12%) as a white solid. LCMS ES (M + H) = 434.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.58 (br.s., 1H), 8.96 (t, J = 4.67 Hz, 1H), 8.38 (s, 1H), 8 .33 (dd, J = 8.84, 5.56 Hz, 2H), 8.16 (s, 1H), 7.40 (t, J = 8.84 Hz, 2H), 5.91 (s, 1H) , 5.33 (dt, J = 13.26, 6.76 Hz, 1H), 4.41 (d, J = 4.55 Hz, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (d, J = 6.57 Hz, 6H).

Example 40
6- {4-[(Dimethylamino) sulfonyl] phenyl} -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (85 mg, 0.23 mmol) and {4-[(dimethylamino) sulfonyl] phenyl} boronic acid (104 mg, 0.46 mmol) were added under nitrogen to DME / water ( 3 mL: 1 mL). PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (9.3 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium bicarbonate (57.3 mg, 0.68 mmol) was added and the insoluble light brown mixture was heated in an oil bath at 110 ° C. for 3 hours. After cooling, 2 mL of water was added and the black mixture and precipitated solid were filtered. DMF was added along with a few drops of water and the solid was filtered. DCM / MeOH (1: 1) was added to the gray solid and they were filtered and dried to give the title compound (69 mg, 57%) as an off-white solid. LCMS ES (M + H) = 523.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.59 (br.s., 1H), 9.01 (br.s., 1H), 8.51 (m, J = 8.34 Hz, 2H) ), 8.44 (s, 1H), 8.27 (s, 1H), 7.93 (m, J = 8.34 Hz, 2H), 5.91 (s, 1H), 5.36 (dt, J = 13.14, 6.57 Hz, 1H), 4.43 (d, J = 4.55 Hz, 2H), 2.66 (s, 6H), 2.23 (s, 3H), 2.13 ( s, 3H), 1.56 (d, J = 6.57 Hz, 6H).

Example 41
6- [6- (Dimethylamino) -3-pyridinyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (80 mg, 0.21 mmol) and [6- (dimethylamino) -3-pyridinyl] boronic acid (53.3 mg, 0.32 mmol) were added under nitrogen. / Water (3 mL: 1 mL). PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (8.7 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed and the insoluble green mixture was irradiated (microwave) at 150 ° C. for 20 minutes. After cooling, 2 mL of water was added and the dark green mixture and precipitated solids were filtered. EtOAc was added and the mixture was heated and some hexane was added. The solid was filtered, dissolved in DCM / MeOH (1: 1), filtered through a pad of silica gel and the filtrate was evaporated. The residue was dissolved in DCM and purified by SiO ₂ chromatography (eluent: gradient 0-90: 10 DCM / MeOH) to give a residual oil that was triturated with EtOH / EtOAc (1: 1). The resulting solid was filtered and dried to give the title compound (46 mg, 45%) as a yellow solid. LCMS ES (M + H) = 460.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.58 (s, 1H), 9.02 (d, J = 2.27 Hz, 1H), 8.87 (t, J = 4.67 Hz, 1H) ), 8.36 (dd, J = 8.84, 2.53 Hz, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 6.79 (d, J = 8.84 Hz) , 1H), 5.91 (s, 1H), 5.25-5.34 (m, 1H), 4.40 (d, J = 4.80 Hz, 2H), 3.12 (s, 6H), 2.23 (s, 3H), 2.13 (s, 3H), 1.53 (d, J = 6.57 Hz, 6H).

Example 42
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- {4-[(methylamino) sulfonyl] phenyl} -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (75 mg, 0.2 mmol), {4-[(methylamino) sulfonyl] phenyl} boronic acid (69 mg, 0.32 mmol) was added to DME / water under nitrogen. (3 mL: 1 mL). PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (8.2 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium bicarbonate (50.6 mg, 0.6 mmol) was added, the vessel was sealed and the insoluble mixture was heated in the microwave at 150 ° C. for 30 minutes.
After cooling, 2 mL of water was added and the mixture and precipitated solid were filtered. DCM / MeOH (1: 1) was added, the solution was filtered through a pad of silica gel and the filtrate was evaporated. The residue was purified by silica gel chromatography (eluent: 0-90: 10 DCM / MeOH gradient) and the isolated solid was triturated in EtOAc. The solid was filtered and dried to give the title compound (29 mg, 28%) as an off-white solid. LCMS ES (M + H) = 509.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ
ppm 11.58 (br.s., 1H), 8.99 (t, J = 4.93 Hz, 1H), 8.47 (m, J = 8.59 Hz, 2H), 8.43 (s, 1H) ), 8.25 (s, 1H), 7.95 (m, J = 8.59 Hz, 2H), 7.60 (br.s., 1H), 5.91 (s, 1H), 5.36. (Quin, J = 6.69 Hz, 1H), 4.42 (d, J = 4.80 Hz, 2H), 2.46 (s, 3H), 2.23 (s, 3H), 2.13 (s , 3H), 1.56 (d, J = 6.82 Hz, 6H).

Example 43
6- (4-Aminophenyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (80 mg, 0.21 mmol) and (4-aminophenyl) boronic acid (44 mg, 0.32 mmol) were added to DME / water (3 mL: 1 mL) under nitrogen. Mixed. PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (8.74 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed, and the insoluble light pink mixture was irradiated (microwave) at 150 ° C. for 30 minutes. After cooling, DCM / MeOH (1: 1) was added, pre-adsorbed onto silica gel and purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH ₄ OH gradient). . The isolated solid was treated with MeOH. The precipitated solid was filtered and dried to give the title compound (63 mg, 66%) as a yellow solid. LCMS ES (M + H) = 431.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.56 (s, 1H), 8.88 (t, J = 4.93 Hz, 1H), 8.27 (s, 1H), 8.01 ( s, 1H), 7.99 (d, J = 2.02 Hz, 2H), 6.69 (s, 1H), 6.67 (s, 1H), 5.90 (s, 1H), 5.61 (S, 2H), 5.24-5.32 (m, 1H), 4.40 (d, J = 4.80 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H) ), 1.53 (s, 3H), 1.51 (s, 3H).

Example 44
6- [4- (Acetylamino) phenyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (80 mg, 0.21 mmol) and [4- (acetylamino) phenyl] boronic acid (57.5 mg, 0.32 mmol) were added under nitrogen with DME / water ( 3 mL: 1 mL). PdCl ₂ (dppf) —CH ₂ Cl ₂ adduct (8.7 mg, 0.010 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed and the light brown mixture was heated at 110 ° C. for 2.5 hours. After cooling, 2 mL of water was added and the dark gray mixture and precipitated solid were filtered. EtOAc was added and the mixture was heated and some hexane was added. The solid was filtered and dissolved in DCM / MeOH (1: 1) and 1 mL DMF. The contents were pre-adsorbed on silica gel and purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH4OH gradient). The isolated product was treated with MeOH and the precipitated solid was filtered, washed with hexane and dried to give the title compound (55 mg, 52%) as a white solid. LCMS ES (M + H) = 473.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ
ppm 11.57 (s, 1H), 10.18 (s, 1H), 8.93 (t, J = 4.93 Hz, 1H), 8.35 (s, 1H), 8.22 (m, J = 8.84 Hz, 2H), 8.13 (s, 1H), 7.76 (m, J = 8.84 Hz, 2H), 5.91 (s, 1H), 5.28-5.37 (m) , 1H), 4.41 (d, J = 4.80 Hz, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 2.09 (s, 3H), 1.54 ( d, J = 6.82 Hz, 6H).

Example 45
6- (3-Aminophenyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (80 mg, 0.21 mmol) and (3-aminophenyl) boronic acid (46.9 mg, 0.34 mmol) were added in DME / water (3 mL: 1 mL) under nitrogen. ). PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (8.74 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed and the reaction mixture was irradiated (microwave) at 150 ° C. for 25 minutes. After cooling, 2 mL of water was added and the black mixture and precipitated solid were filtered. DCM / MeOH (1: 1) was added and the mixture was pre-adsorbed onto silica gel and purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH4OH gradient). The isolated product was treated with EtOH / EtOAc / hexane (1: 1: 1). The precipitated solid was filtered and dried to give the title compound (40 mg, 42%) as a light gray solid. LCMS ES (M + H) = 431.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ
ppm 11.56 (br.s., 1H), 8.96 (t, J = 4.93 Hz, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 7.46 ( t, J = 1.89 Hz, 1H), 7.36 (d, J = 7.58 Hz, 1H), 7.18 (t, J = 7.71 Hz, 1H), 6.69 (dd, J = 7 .83, 1.52 Hz, 1H), 5.90 (s, 1H), 5.25-5.37 (m, 3H), 4.40 (d, J = 4.80 Hz, 2H), 2.22 (S, 3H), 2.13 (s, 3H), 1.55 (s, 3H), 1.54 (s, 3H).

Example 46
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- {4-[(methylamino) carbonyl] phenyl} -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

The title compound was prepared in the same manner as described in Example 61 using {4-[(methylamino) carbonyl] phenyl} boronic acid (57.5 mg, 0.32 mmol) to produce a light gray solid (70 mg, 68%) was obtained. LCMS ES (M + H) = 473.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.58 (s, 1H), 9.00 (t, J = 4.80 Hz, 1H), 8.59 (q, J = 4.38 Hz, 1H) ), 8.41 (s, 1H), 8.35 (m, J = 8.59 Hz, 2H), 8.24 (s, 1H) 8.01 (m, J = 8.59 Hz, 2H), 5 .91 (s, 1H), 5.33-5.41 (m, 1H), 4.42 (d, J = 4.80 Hz, 2H), 2.83 (d, J = 4.55 Hz, 3H) , 2.23 (s, 3H), 2.13 (s, 3H), 1.56 (s, 3H), 1.55 (s, 3H).

Example 47
6- [3- (acetylamino) phenyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (80 mg, 0.21 mmol) and [3- (acetylamino) phenyl] boronic acid (57.5 mg, 0.32 mmol) were added under nitrogen with DME / water ( 3 mL: 1 mL). PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (8.7 mg, 0.010 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed and the reaction mixture was irradiated (microwave) at 150 ° C. for 30 minutes. After cooling, 2 mL of water was added and the precipitated solid was filtered. DCM / MeOH (1: 1) was added and the mixture was pre-adsorbed onto silica gel and purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH ₄ OH gradient). The isolated product was treated with EtOH and DCM, filtered and dried to give the title compound (65 mg, 63%) as a white solid. LCMS ES (M + H) = 473.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.58 (s, 1H), 9.02 (t, J = 4.80 Hz, 1H), 8.61-8.68 (m, 2H), 8.37-8.43 (m, 2H), 8.21 (s, 1H), 7.94 (d, J = 7.83 Hz, 1H), 7.65 (t, J = 7.83 Hz, 1H) ), 5.91 (s, 1H), 5.37 (quin, J = 6.63 Hz, 1H), 4.42 (d, J = 4.80 Hz, 2H), 2.84 (d, J = 4) .29 Hz, 3H), 2.24 (s, 3H), 2.13 (s, 3H), 1.57 (s, 3H), 1.55 (s, 3H).

Example 48
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl) -1- (1-Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (80 mg, 0.21 mmol) and (2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl) boronic acid (50 mg, 0.32 mmol) ) Was combined with DME / water (3 mL: 1 mL) under nitrogen. PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (8.74 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed and the reaction mixture was heated in the microwave at 150 ° C. for 30 minutes. After cooling, 2 mL of water was added and the black mixture and precipitated solid were filtered. DCM / MeOH (1: 1) was added and the mixture was pre-adsorbed onto silica gel and purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH ₄ OH gradient). The isolated product was treated with EtOH / EtOAc (1: 1) and sonicated. The precipitated solid was filtered, washed with EtOH and DCM and dried to give the title compound (41 mg, 42%) as a light gray solid. LCMS ES (M + H) = 449.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.58 (s, 1H), 11.52 (br.s., 1H), 11.47 (s, 1H), 8.75 (t, J = 5.05 Hz, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 5.90 (s, 1H), 5.27 (quin, J = 6.69 Hz, 1H), 4.37 (d, J = 0.05 Hz, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.52 (s, 3H) , 1.50 (s, 3H).

Example 49
6- (2-Amino-4-pyridinyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

The title compound was prepared using 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyridinamine (65.9 mg, 0.3 mmol). Prepared in the same manner as described in Example 48 to give an off-white solid (60 mg, 73%). LCMS ES (M + H) = 432.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (s, 1H), 8.99 (t, J = 4.80 Hz, 1H), 8.41 (s, 1H), 8.05- 8.13 (m, 2H), 7.24-7.32 (m, 2H), 6.14 (s, 2H), 5.91 (s, 1H), 5.33 (quin, J = 6. 69 Hz, 1H), 4.41 (d, J = 4.80 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H), 1.55 (d, J = 6.57 Hz, 6H).

Example 50
6- [4- (Aminosulfonyl) phenyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

The title compound was prepared in the same manner as described in Example 48 using [4- (aminosulfonyl) phenyl] boronic acid (64.5 mg, 0.32 mmol) to produce a light gray solid (76 mg, 74%). LCMS ES (M + H) = 495.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.58 (br.s., 1H), 8.99 (t, J = 4.80 Hz, 1H), 8.41-8.48 (m, 3H), 8.25 (s, 1H), 8.00 (d, J = 8.59 Hz, 2H), 7.50 (s, 2H), 5.91 (s, 1H), 5.37 (quin) , J = 6.69 Hz, 1H), 4.43 (d, J = 4.80 Hz, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 1.56 (d, J = 6.57 Hz, 6H).

Example 51
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- {4-[(methylsulfonyl) amino] phenyl} -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (75 mg, 0.2 mmol) and {4-[(methylsulfonyl) amino] phenyl} boronic acid (43.1 mg, 0.2 mmol) were added to DME under nitrogen. / Water (3 mL: 1 mL). PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (8.2 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium bicarbonate (50.6 mg, 0.6 mmol) was added, the vessel was sealed, and the reaction mixture was irradiated (microwave) at 150 ° C. for 25 minutes. After cooling, 2 mL of water was added and the black mixture and precipitated solid were filtered. DCM / MeOH (1: 1) was added and the mixture was pre-adsorbed onto silica gel and purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH4OH gradient). The isolated product was suspended in EtOAc, heated and sonicated. Some hexane was added and the contents were cooled to room temperature. The precipitated solid was filtered. The solid was then suspended in EtOH, heated and sonicated. After cooling to room temperature, the solid was filtered and dried to give the title compound (38 mg, 36%) as a beige solid. LCMS ES (M + H) = 509.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (s, 1H), 10.05 (br.s., 1H), 8.93 (t, J = 4.93 Hz, 1H), 8 .35 (s, 1H), 8.24 (m, J = 8.59 Hz, 2H), 8.11 (s, 1H), 7.37 (m, J = 8.84 Hz, 2H), 5.91 (S, 1H), 5.32 (quin, J = 6.69 Hz, 1H), 4.41 (d, J = 4.80 Hz, 2H), 3.08 (s, 3H), 2.23 (s , 3H), 2.13 (s, 3H), 1.55 (s, 3H), 1.54 (s, 3H).

Example 52
6- {4-[(Dimethylamino) sulfonyl] phenyl} -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1 -Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl ) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide (75 mg, 0.19 mmol) and N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl) benzenesulfonamide (90 mg, 0.29 mmol) was combined with DME / water (3 mL: 1 mL) under nitrogen. PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (7.9 mg, 0.009 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. Sodium bicarbonate (48.7 mg, 0.58 mmol) was added, the vessel was sealed and the reaction mixture was irradiated (microwave) at 150 ° C. for 30 minutes. After cooling, 2 mL of water was added and the precipitated solid was filtered. DCM / MeOH (1: 1) was added and the mixture was pre-adsorbed onto silica gel and purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH ₄ OH gradient). The isolated product is treated with EtOH / EtOAc (1: 1) and the solid is filtered, washed with EtOAc and DCM, then dried to give the title compound (83 mg, 78%) as a white solid. It was. LCMS ES (M + H) = 537.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.54 (s, 1H) 8.79 (t, J = 4.93 Hz, 1H) 8.47 (m, J = 8.59 Hz, 2H) 7 .90 (m, J = 8.59 Hz, 2H) 7.80 (s, 1H) 5.89 (s, 1H) 5.28 (quin, J = 6.69 Hz, 1H) 4.40 (d, J = 5.05 Hz, 2H) 2.66 (s, 6H) 2.47 (s, 3H) 2.25 (s, 3H) 2.12 (s, 3H) 1.53 (s, 3H) 1.51 (S, 3H).

Example 53
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-piperidinylamino) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (60 mg, 0.16 mmol) and 4-piperidineamine (2 mL) were combined with EtOH (3 mL) under nitrogen. The vessel was sealed and the reaction mixture was irradiated (microwave) at 125 ° C. for 5 hours and then at 160 ° C. for 90 minutes. The mixture was evaporated under vacuum and the resulting residue was partitioned between EtOAc and water. The organics were washed with water (2 ×) and brine, dried over MgSO ₄ , filtered and evaporated. The residue was chromatographed on silica gel (eluent: 0-90: 10: 1
Purified by DCM / MeOH / NH ₄ OH gradient). The isolated product was treated with EtOAc / ether (1: 1) and left at room temperature overnight. The precipitated solid was triturated, filtered and dried to give the title compound as a pale yellow solid 25 mg (35%). LCMS ES (M + H) = 438.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.66 (t, J = 4.67 Hz, 1H) 7.98 (s, 1H) 7.12 (s, 1H) 5.89 (s, 1H ) 4.98 (dt, J = 13.33, 6.60 Hz, 1H) 4.30-4.41 (m, 4H) 3.01 (t, J = 11.62 Hz, 2H) 2.85 (br .S., 1H) 2.20 (s, 3H) 2.12 (s, 3H) 1.80 (d, J = 10.36 Hz, 2H) 1.44 (s, 3H) 1.43 (s, 3H) 1.18-1.30 (m, 3H) 0.79-0.91 (m, 1H)

Example 54
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (tetrahydro-2H-pyran-4-ylamino)- 1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (60 mg, 0.16 mmol) and tetrahydro-2H-pyran-4-amine (2 mL, 19 mmol) were combined with EtOH (3 mL) under nitrogen. The vessel was sealed and the reaction mixture was irradiated (microwave) at 125 ° C. for 2 hours and then at 170 ° C. for 1 hour. The mixture was concentrated to about 20% volume and NMP (2 mL) was added to the reaction mixture. The contents were first irradiated again (microwave) at 180 ° C. for 2.5 hours and then irradiated at 190 ° C. for 75 minutes. The mixture was evaporated under vacuum and the resulting residue was purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH ₄ OH gradient). The isolated product was treated with EtOAc / hexane (1: 1), sonicated and heated. After cooling, the precipitated solid was filtered and dried to give the title compound (46 mg, 64%) as an off-white solid. LCMS ES (M + H) = 439.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.55 (s, 1H) 8.44 (t, J = 0.05 Hz, 1H) 7.83 (s, 1H) 7.20 (d, J = 7.33 Hz, 1H) 6.63 (s, 1H) 5.89 (s, 1H) 4.93 (quin, J = 6.69 Hz, 1H) 4.32 (d, J = 0.05 Hz, 2H) 3.99-4.06 (m, 1H) 3.88 (dt, J = 11.49, 3.47 Hz, 2H) 3.45 (td, J = 11.37, 2.02 Hz, 2H) 2 .21 (s, 3H) 2.13 (s, 3H) 1.95 (d, J = 10.61 Hz, 2H) 1.41-1.51 (m, 8H).

Example 55
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-[(4-pyridinylmethyl) amino] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (60 mg, 0.16 mmol) and (4-pyridinylmethyl) amine (0.065 mL, 0.64 mmol) were combined with EtOH (2 mL) under nitrogen. The vessel was sealed and the reaction mixture was heated at 90 ° C. overnight. An additional 1 mL of (4-pyridinylmethyl) amine was added and the mixture was heated in the microwave at 160 ° C. for 90 minutes. EtOH solvent was removed under reduced pressure, 2 mL of NMP was added, and the mixture was then irradiated (microwave) at 180 ° C. for 90 minutes. The mixture was evaporated under vacuum and the resulting residue was partitioned between EtOAc and water. The crude residue was extracted with EtOAc, DCM and DCM / isopropanol (70:30). The combined organics were washed with water (2 ×) and brine, dried over MgSO ₄ , filtered and evaporated. The residue was purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH ₄ OH gradient). The isolated yellow oil was treated with EtOAc and sonicated. The filtered solid was washed with hexane and dried to give the title compound (26 mg, 36%) as a white solid. LCMS ES (M + H) = 446.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.56 (s, 1H) 8.50 (t, J = 5.18 Hz, 1H) 8.43-8.48 (m, 2H) 7.89 (T, J = 5.94 Hz, 1H) 7.84 (s, 1H) 7.34 (d, J = 6.06 Hz, 2H) 6.73 (s, 1H) 5.89 (s, 1H) 4 .83 (quin, J = 6.69 Hz, 1H) 4.58 (d, J = 5.81 Hz, 2H) 4.32 (d, J = 5.05 Hz, 2H) 2.21 (s, 3H) 2 .13 (s, 3H) 1.32 (d, J = 6.82 Hz, 6H).

Example 56
6-{[2- (Dimethylamino) ethyl] amino} -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (80 mg, 0.21 mmol) and (2-aminoethyl) dimethylamine (37.7 mg, 0.43 mmol) were mixed in NMP (2 mL) under nitrogen. Combined. The vessel was sealed and the reaction mixture was irradiated (microwave) at 150 ° C. for 1 hour. The mixture was evaporated under vacuum and the resulting residue was partitioned between EtOAc and water. The contents were extracted with EtOAc, DCM and DCM / isopropanol (70:30). The combined organics were washed with water (2 ×) and brine, dried over MgSO ₄ , filtered and evaporated. The residue was purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH ₄ OH gradient). The isolated yellow oil was treated with EtOAc and sonicated. The precipitated solid was filtered, washed with hexane and dried to give the title compound (60 mg, 65%) as a white solid. LCMS ES (M + H) = 425.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.55 (br.s., 1H) 8.43 (t, J = 0.05 Hz, 1H) 7.84 (s, 1H) 7.08 ( t, J = 5.05 Hz, 1H) 6.67 (s, 1H) 5.89 (s, 1H) 4.94 (quin, J = 6.63 Hz, 1H) 4.32 (d, J = 5. 05 Hz, 2H) 3.44 (q, J = 6.48 Hz, 2H) 2.44 (t, J = 6.69 Hz, 2H) 2.17-2.22 (m, 9H) 2.12 (s, 3H) 1.43 (d, J = 6.57 Hz, 6H).

Example 57
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6-[(2-hydroxyethyl) amino] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

In a 25 mL sealable tube, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide (80 mg, 0.21 mmol) and 2-aminoethanol (1 mL) were combined with NMP (2 mL) under nitrogen.
The vessel was sealed and the reaction mixture was irradiated (microwave) at 130 ° C. for 1 hour and then at 140 ° C. for 90 minutes. The mixture was evaporated under vacuum and the residue was purified by silica gel chromatography (eluent: 0-90: 10: 1 DCM / MeOH / NH 4 OH gradient. The isolated yellow oil was treated with EtOAc and sonicated. And treated with hexane.
The solid was filtered and dissolved in DMF (1 mL) and a few drops of water were added. The solution was left at room temperature overnight and then sonicated. The filtered solid was washed with hexanes / EtOAc (1: 1) and then dried to give the title compound (55 mg, 63%) as a pale yellow solid. LCMS ES (M + H) = 399.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm
11.56 (br.s., 1H) 8.44 (br.s., 1H) 7.84 (s, 1H) 7.20 (br.s., 1H) 6.68 (s, 1H) 5 .89 (s, 1H) 4.95 (dt, J = 13.01, 6.38 Hz, 1H) 4.72 (t, J = 4.93 Hz, 1H) 4.32 (d, J = 4.80 Hz) , 2H) 3.58 (d, J = 5.56 Hz, 2H) 3.38-3.46 (m, 2H) 2.21 (s, 3H) 2.12 (s, 3H) 1.43 (d , J = 6.57Hz, 6H)

Example 58
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [5- (methyloxy) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

In a 20 mL microwave vial, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (100 mg, 0.267 mmol, 3- (methyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Pyridine (69.2 mg, 0.294 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (21.84 mg, 0.027 mmol), (DME) (5 mL), and water (2 mL) were added sequentially. The reaction mixture was degassed with nitrogen for 5 minutes.
Sodium bicarbonate (67.4 mg, 0.802 mmol) was added and the contents sealed and irradiated (microwave) at 140 ° C. The reaction mixture was cooled to room temperature, poured onto a silica column (through Na ₂ SO ₄ ), purified by silica gel chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ), precipitated from EtOAc / MeOH, and then desired The product was obtained as an off-white solid. 0.090 g (76%) of the final product was recovered. LCMS ES (M + H) 447.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (s., 1H), 9.06 (d, J = 1.52 Hz, 1H), 8.92-9.00 (m, 1H) 8.39-8.48 (m, 2H), 8.24 (s, 1H), 8.14 (d, J = 1.77 Hz, 1H), 5.91 (s, 1H), 5.30. −5.45 (m, 1H), 4.42 (d, J = 4.80 Hz, 2H), 3.97 (s, 3H), 2.24 (s, 3H), 2.13 (s, 3H) ), 1.55 (d, J = 6.82 Hz, 6H).

Example 59
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [2- (methyloxy) -4-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

The title compound was prepared in the same way as described in Example 58 using 2-methoxypyridine-4-boronic acid pinacol ester (69.2 mg, 0.294 mmol), evaporated from EtOAc / MeOH, precipitated After that, the desired product was obtained as a gray solid. 0.051 g (41%) of the final product was recovered. LCMS ES (M + H) 447.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (br.s., 1H) 9.00 (t, J = 4.80 Hz, 1H) 8.44 (s, 1H) 8.36 ( s, 1H) 8.26 (s, 1H) 7.84 (dd, J = 5.31, 1.52 Hz, 1H) 7.67 (s, 1H) 5.91 (s, 1H) 5.32- 5.40 (m, 1H) 4.42 (d, J = 4.80 Hz, 2H) 3.94 (s, 3H) 2.23 (s, 3H) 2.13 (s, 3H) 1.55 ( d, 6H).

Example 60
6- (6-Amino-3-pyridinyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

The title compound was prepared in the same manner as described in Example 58 using 6-aminopyridine-3-boronic acid pinacol ester (64.8 mg, 0.294 mmol), evaporated from EtOAc / MeOH, precipitated After that, the desired product was obtained as a gray solid. 0.060 g (49%) of the final product was recovered. LCMS ES (M + H) = 432.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (br.s., 1H) 8.85-8.92 (m, 2H) 8.31 (s, 1H) 8.26 (dd, J = 8.59, 2.53 Hz, 1H) 8.04 (s, 1H) 6.57 (d, J = 8.59 Hz, 1H) 6.46 (s, 2H) 5.90 (s, 1H) 5.25-5.33 (m, 1H) 4.40 (d, J = 4.80 Hz, 2H) 2.22 (s, 3H) 2.13 (s, 3H) 1.53 (d, 6H) .

Example 61
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [5- (methylsulfonyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

The title compound was prepared in the same manner as described in Example 58 using [5- (methylsulfonyl) -3-pyridinyl] boronic acid (59.1 mg, 0.294 mmol) and was prepared from EtOAc / MeOH. After evaporation and precipitation, the desired product was obtained as an off-white solid. 0.079 g (59%) of the final product was recovered. LCMS ES (M + H) = 495.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.59 (br.s., 1H), 9.76 (d, J = 2.27 Hz, 1H), 9.21 (d, J = 2. 02Hz, 1H), 9.00-9.06 (m, 2H), 8.46 (s, 1H), 8.37 (s, 1H), 5.91 (s, 1H), 5.36-5 .44 (m, 1H), 4.43 (d, J = 4.80 Hz, 2H), 3.45 (s, 3H), 2.24 (s, 3H), 2.13 (s, 3H), 1.56 (d, 6H).

Example 62
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (2-furanyl) -1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

The title compound is described in Example 74 using 2- (2-furanyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (57.1 mg, 0.294 mmol). Prepared in the same manner as the method and after evaporation and precipitation from EtOAc / MeOH, the desired product was obtained as a white solid. 0.049 g (44%) of the final product was recovered. LCMS ES (M + H) 406.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (s, 1H) 8.93 (t, J = 4.93 Hz, 1H) 8.33 (s, 1H) 7.97 (s, 1H ) 7.94 (d, J = 1.01 Hz, 1H) 7.34 (d, J = 2.78 Hz, 1H) 6.73 (dd, J = 3.54, 1.77 Hz, 1H) 5.90 (S, 1H) 5.19-5.32 (m, 1H) 4.39 (d, J = 4.80 Hz, 2H) 2.23 (s, 3H) 2.13 (s, 3H) 1.52 (D, 6H).

Example 63
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- {6-[(methylamino) carbonyl] -3-pyridinyl} -1- (1- Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

The title compound was prepared in the same manner as described in Example 58 using 2- (N-methylamidocarboxy) -5-pyridineboronic acid pinacol ester (70.1 mg, 0.267 mmol) and EtOAc. After evaporation / precipitation from / MeOH, the desired product was obtained as an off-white solid. 0.080 g (60%) of the final product was recovered. LCMS ES (M + H) = 474.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.59 (br.s., 1H), 9.46 (d, J = 1.52 Hz, 1H), 8.98 (t, J = 4. 55 Hz, 1H), 8.85 (d, J = 0.05 Hz, 1H), 8.78 (dd, J = 8.21, 2.15 Hz, 1H), 8.44 (s, 1H), 8. 31 (s, 1H), 8.20 (d, J = 8.08 Hz, 1H), 5.91 (s, 1H), 5.30-5.42 (m, 1H), 4.42 (d, J = 4.55 Hz, 2H), 2.87 (d, J = 4.80 Hz, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 1.56 (d, 6H) .

Example 64
6- [5-[(Cyclopropylsulfonyl) amino] -6- (methyloxy) -3-pyridinyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) Methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

N- [2- (methyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridinyl] cyclopropanesulfonamide (95 mg, 0. The title compound was prepared in the same manner as described in Example 58 using 267 mmol) to give the desired product as an off-white solid after evaporation and precipitation from EtOAc / MeOH. 0.100 g (66%) of the final product was recovered. LCMS ES (M + H) 566.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ · ppm 11.57 (s, 1H) 9.47 (s, 1H) 8.94 (t, J = 4.93 Hz, 1H) 8.89 (d, J = 2.27 Hz, 1H) 8.49 (d, J = 2.27 Hz, 1H) 8.37 (s, 1H) 8.15 (s, 1H) 5.91 (s, 1H) 5.29 (m , 1H) 4.41 (d, J = 4.80 Hz, 2H) 4.01 (s, 3H) 2.70-2.78 (m, 1H) 2.23 (s, 3H) 2.13 (s , 3H) 1.56 (d, J = 6.57 Hz, 6H) 0.91-1.00 (m, 4H).

Example 65
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- {5-[(phenylsulfonyl) amino] -3 -Pyridinyl} -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

N- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridinyl] benzenesulfonamide (96 mg, 0.267 mmol) was used to give the title The compound was prepared in the same manner as described in Example 58 and after evaporation and precipitation from EtOAc / MeOH, the desired product was obtained as an off-white solid. 0.050 g (33%) of the final product was recovered. LCMS ES (M + H) = 572.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (s, 1H), 10.83 (s, 1H), 9.10 (d, J = 1.77 Hz, 1H), 8.95 ( t, J = 0.05 Hz, 1H), 8.37-8.45 (m, 2H), 8.32 (t, J = 2.15 Hz, 1H), 8.17 (s, 1H), 7. 82-7.91 (m, 2H), 7.55-7.69 (m, 3H), 5.90 (s, 1H), 5.18-5.30 (m, 1H), 4.41 ( d, J = 5.05 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H), 1.58 (d, J = 6.82 Hz, 6H).

Example 66
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [2- (4-morpholinyl) -4-pyridinyl ] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyridinyl] morpholine (78 mg, 0.267 mmol) was used to give the title compound. Prepared in the same manner as described in Example 58, and after evaporation and precipitation from EtOAc / MeOH, the desired product was obtained as an off-white solid. 0.110 g (58%) of the final product was recovered. LCMS ES (M + H) 502.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (s, 1H), 8.95 (t, J = 0.05 Hz, 1H), 8.40 (s, 1H), 8.31 ( d, J = 5.30 Hz, 1H), 8.18 (s, 1H), 7.58 (s, 1H), 7.51 (dd, J = 5.31, 1.26 Hz, 1H), 5. 90 (s, 1H), 5.39-5.30 (m, 1H), 4.42 (d, J = 4.80 Hz, 2H), 3.72-3.80 (m, 4H), 3. 54-3.62 (m, 4H), 2.24 (s, 3H), 2.13 (s, 3H), 1.55 (d, J = 6.57 Hz, 6H).

Example 67
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [6- (4-morpholinyl) -3-pyridinyl ] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

The title compound was prepared in the same manner as described in Example 58 using 6-morpholinopyridine-3-boronic acid (55.6 mg, 0.267 mmol), after evaporation and precipitation from EtOAc / MeOH The desired product was obtained as an off-white solid. 0.110 g (82%) of the final product was recovered. LCMS ES (M + H) 502.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (s, 1H), 9.06 (d, J = 2.27 Hz, 1H), 8.88 (t, J = 4.93 Hz, 1H) , 8.41 (dd, J = 8.97, 2.40 Hz, 1H), 8.33 (s, 1H), 8.11 (s, 1H), 7.00 (d, J = 9.09 Hz, 1H), 5.91 (s, 1H), 5.34-5.28 (m, 1H), 4.40 (d, J = 4.80 Hz, 2H), 3.71-3.78 (m, 4H), 3.55-3.62 (m, 4H), 2.23 (s, 3H), 2.13 (s, 3H), 1.54 (d, J = 6.82 Hz, 6H).

Example 68
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [6- (methyloxy) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

The title compound was prepared in the same manner as described in Example 58 using [6- (methyloxy) -3-pyridinyl] boronic acid (40.9 mg, 0.267 mmol) and was prepared from EtOAc / MeOH. After evaporation and precipitation, the desired product was obtained as an off-white solid. 0.060 g (50%) of the final product was recovered. LCMS ES (M + H) 447.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.58 (s, 1H), 9.07 (d, J = 2.02 Hz, 1H), 8.90 (t, J = 4.93 Hz, 1H) ), 8.55 (dd, J = 8.59, 2.53 Hz, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 7.01 (d, J = 8.84 Hz) , 1H), 5.91 (s, 1H), 5.36-5.28 (m, 1H), 4.41 (d, J = 0.05 Hz, 2H), 3.95 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (d, J = 6.57 Hz, 6H).

Example 69
6- [6- (acetylamino) -3-pyridinyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

The title compound was prepared in the same manner as described in Example 58 using 2-acetamidopyridine-5-boronic acid pinacol ester (77 mg, 0.294 mmol), after evaporation and precipitation from EtOAc / MeOH The desired product was obtained as an off-white solid. 0.065 g (51%) of the final product was recovered. LCMS ES (M + H) = 474.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (s, 1H), 10.76 (s, 1H), 9.19 (d, J = 1.77 Hz, 1H), 8.93 ( t, J = 4.80 Hz, 1H), 8.61 (dd, J = 8.84, 2.27 Hz, 1H), 8.38 (s, 1H), 8.25 (d, J = 8.84 Hz) , 1H), 8.20 (s, 1H), 5.91 (s, 1H), 5.30-5.40 (m, 1H), 4.42 (d, J = 0.05 Hz, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 2.13 (s, 3H), 1.54 (d, J = 6.82 Hz, 6H).

Example 70
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-methylphenyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide

The title compound is prepared in the same manner as described in Example 58 using 2-methylphenylboronic acid (40.0 mg, 0.294 mmol), evaporated from MeOH, precipitated, and the desired product Was obtained as an off-white solid. 0.065 g (51%) of the final product was recovered. LCMS ES (M + H) = 430.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.54 (s, 1H) 8.89 (t, J = 4.93 Hz, 1H) 8.39 (s, 1H) 7.74 (s, 1H ) 7.56 (d, J = 7.07 Hz, 1H) 7.31-7.41 (m, 3H) 5.89 (s, 1H) 5.20-5.27 (m, 1H) 4.38 (D, J = 4.80 Hz, 2H) 2.40 (s, 3H) 2.21 (s, 3H) 2.12 (s, 3H) 1.53 (d, 6H).

Example 71
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (1H-pyrazol-4-yl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

In a 5 mL microwave vial, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (70 mg, 0.187 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole ( 47.2 mg, 0.243 mmol), DMSO (1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol) were added and the mixture was degassed with nitrogen for 5 min. Next, bis (triphenylphosphine) palladium (II) chloride (10.51 mg, 0.015 mmol) was added and the vial was sealed. The mixture was irradiated (microwave) at 140 ° C. for 12 hours. The reaction mixture was filtered and the residue was washed with DMSO. The crude product in DMSO was purified using reverse phase HPLC. The resulting TFA salt of the product was neutralized with saturated NaHCO ₃ , washed with water and dried under high vacuum to give 12 mg (16%) of product. LCMS: (M + H) + = 406.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.45-1.60 (m, J = 6.4 Hz, 6H), 2.13 (s, 3H) 2.23 (s, 3H), 4.39 (d, J = 4.6 Hz, 2H), 5.27 (quin, J = 6.7 Hz, 1H), 5.90 (s, 1H), 7 .91 (s, 1H), 8.22-8.31 (m, 1H), 8.33 (m, 2H), 8.77 (t, J = 4.7 Hz, 1H).

Example 72
6- (2-Amino-5-pyrimidinyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

DMSO (2 mL) was added to a 5 mL microwave vial and it was degassed with nitrogen for 5 min. Next, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide (70 mg, 0.187 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyrimidinamine (49. 7 mg, 0.225 mmol), sodium carbonate (59.5 mg, 0.562 mmol) and bis (triphenylphosphine) palladium (II) chloride (9.20 mg, 0.013 mmol) were added. The mixture was degassed for an additional 5 minutes, sealed and irradiated (microwave) at 135 ° C. for 15 hours. The mixture was filtered and the residue was washed with DMSO. The crude product in DMSO was purified using reverse phase HPLC. The TFA salt of the product was neutralized with saturated NaHCO ₃ solution, filtered, washed with water and dried under high vacuum to give 14 mg (17%) of product. LCMS ES (M + H) = 433.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.52 (d, J = 6.4 Hz, 6H), 2.13 (s, 3H), 2. 22 (s, 3H), 4.40 (d, J = 4.6 Hz, 2H) 5.22-5.41 (m, 1H), 5.90 (s, 1H), 7.18 (m, 2H) ), 8.08 (s, 1H), 8.34 (s, 1H), 8.86 (m, 1H), 9.11 (s, 2H), 11.58 (br.s., 1H).

Example 73
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (3-pyridinyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

In a 5 mL microwave vial, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (70 mg, 0.187 mmol), 3-pyridinylboronic acid (29.9 mg, 0.243 mmol), DMSO (1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol) ) And the mixture was degassed with nitrogen for 10 minutes. Next, bis (triphenylphosphine) palladium (II) chloride (10.51 mg, 0.015 mmol) was added and the vial was sealed. The reaction mixture was irradiated (microwave) at 140 ° C. overnight. The reaction mixture was filtered and the residue was washed with DMSO. The crude product in DMSO was purified using reverse phase HPLC. The TFA salt of the product was neutralized with saturated NaHCO ₃ solution, filtered, washed with water and dried under high vacuum to give 33 mg (42%) of product. LCMS ES (M + H) = 417.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.56 (d, J = 6.4 Hz, 6H), 2.13 (s, 3H), 2. 23 (s, 3H), 4.42 (d, J = 4.29 Hz, 2H), 5.26-5.43 (m, 1H), 5.91 (s, 1H), 7.62 (dd, J = 7.3, 5.0 Hz, 1H), 8.26 (s, 1H), 8.43 (s, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.70−. 8.79 (m, 1H), 8.96 (br.s., 1H), 9.46 (br.s., 1H), 11.59 (br.s., 1H).

Example 74
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (1H-indazol-5-yl) -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

In a 5 mL microwave vial, add 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (70 mg, 0.187 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole ( 59.4 mg, 0.243 mmol), DMSO (1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol) were added and the mixture was degassed with nitrogen for 10 min. Next, bis (triphenylphosphine) palladium (II) chloride (10.51 mg, 0.015 mmol) was added. The contents were sealed and irradiated (microwave) at 140 ° C. overnight. The reaction mixture was filtered and the residue was washed with DMSO. The crude product in DMSO was purified using reverse phase HPLC. The TFA salt of the product was neutralized with saturated NaHCO ₃ solution, filtered, washed with water and dried under high vacuum to give 41 mg (48%) of product. LCMS ES (M + H) = 456.0 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.56 (d, J = 6.8 Hz, 6H), 2.14 (s, 3H), 2. 23 (s, 3H), 4.38-4.53 (m, 2H), 5.27-5.49 (m, 1H), 5.91 (s, 1H), 7.59-7.75 ( m, 1H), 8.24 (s, 2H), 8.37 (s, 2H), 8.69 (s, 1H), 8.95-9.09 (m, 1H), 11.49-11 .67 (m, 1H), 13.21-13.35 (m, 1H).

Example 75
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (1H-indazol-6-yl) -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (70 mg, 0.187 mmol), 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (59.4 mg, 0. 243 mmol), DMSO (1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis (triphenylphosphine) palladium (II) chloride (10.51 mg, 0.015 mmol). Prepared in the same manner as described in Example 74. 55 mg (65%) of the final product was recovered. LCMS ES (M + H) = 456.0 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.49-1.65 (m, J = 6.4 Hz, 6H), 2.14 (s, 3H ), 2.23 (s, 3H), 4.43 (d, J = 4.6 Hz, 2H), 5.36 (quin, J = 6.7 Hz, 1H), 5.87-5.97 (m) , 1H), 7.52-7.72 (m, 2H) 7.92 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.16 ( s, 1H), 8.26 (s, 1H), 8.37-8.49 (m, 2H), 8.96-9.14 (m, 1H), 11.59 (br.s., 1H) ).

Example 76
6- (1H-1,2,3-benzotriazol-5-yl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1 -Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (70 mg, 0.187 mmol), 1H-1,2,3-benzotriazol-5-ylboronic acid (39.7 mg, 0.243 mmol), DMSO (2 mL), sodium carbonate (0.281 mL, The title compound was prepared in the same manner as described in Example 74 using 0.562 mmol) and bis (triphenylphosphine) palladium (II) chloride (10.51 mg, 0.015 mmol). 22 mg (26%) of the final product was recovered. LCMS ES (M + H) = 457.1 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.57 (d, 6J = 6.4 Hz, H), 2.14 (s, 3H), 2. 24 (s, 3H), 4.43 (d, J = 4.3 Hz, 2H), 5.31-5.46 (m, 1H), 5.91 (s, 1H), 8.07 (br. s., 1H), 8.34 (s, 1H), 8.41 (m, 2H), 8.85 (br.s., 1H), 9.02 (br.s., 1H), 11. 59 (br.s., 1H).

Example 77
N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -6- (2-oxo-2,3 -Dihydro-1H-benzimidazol-5-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (70 mg, 0.187 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3-dihydro-2H-benzimidazole 2-one (61.0 mg, 0.235 mmol), DMSO (1.5 mL) sodium carbonate (0.281 mL, 0.562 mmol), and bis (triphenylphosphine) palladium (II) chloride (10.13 mg, 0 .014 mmol) was used to prepare the title compound in the same manner as described in Example 74. 19 mg (21%) of the final product was recovered. LCMS ES (M + H) = 486.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.50 (d, J = 6.8 Hz, 6H), 2.12 (s, 3H), 2. 24 (s, 3H), 2.43 (s, 3H), 4.39 (d, J = 4.6 Hz, 2H), 5.15-5.35 (m, 1H), 5.89 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.77-7.93 (m, 2H), 8.70-8.85 (m, 1H), 10.79 (br.s., 1H), 10.87 (br.s., 1H), 11.54 (br.s., 1H).

Example 78
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-oxo-2,3-dihydro-1H -Indol-6-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (70 mg, 0.187 mmol), 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3-dihydro-2H-indole- 2-one (63.1 mg, 0.243 mmol), DMSO (1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis (triphenylphosphine) palladium (II) chloride (10.51 mg, 0 The title compound was prepared in the same manner as described in Example 74. 10 mg (11%) of the final product was recovered. LCMS ES (M + H) = 471.1 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.55 (d, J = 6.8 Hz, 6H), 2.13 (s, 3H), 2. 22 (s, 3H), 3.58 (s, 2H), 4.41 (d, J = 4.8 Hz, 2H), 5.31 (quin, J = 6.6 Hz, 1H), 5.91 ( s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 1.0 Hz, 1H), 7.87 (dd, J = 7.8, 1.5 Hz) , 1H), 8.12 (s, 1H), 8.37 (s, 1H), 9.00 (t, J = 4.8 Hz, 1H), 10.55 (s, 1H), 11.58 ( s, 1H).

Example 79
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-oxo-2,3-dihydro-1H -Indol-5-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (70 mg, 0.187 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3-dihydro-2H-indole- 2-one (63.1 mg, 0.243 mmol), DMSO (1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis (triphenylphosphine) palladium (II) chloride (10.51 mg, 0 The title compound was prepared in the same manner as described in Example 74. 30 mg (34%) of the final product was recovered. LCMS ES (M + H) = 471.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.54 (d, J = 6.4 Hz, 6H), 2.13 (s, 3H), 2. 22 (s, 3H), 3.40 (br.s., 2H), 4.41 (d, J = 4.6 Hz, 2H), 5.25-5.41 (m, 1H), 5.91 (S, 1H), 6.97 (d, J = 8.1 Hz, 1H), 8.08-8.21 (m, 3H), 8.34 (s, 1H), 8.96 (br.s) , 1H), 10.64 (s, 1H), 11.58 (br.s., 1H).

Example 80
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-oxo-2,3-dihydro-1H -Benzimidazol-5-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (70 mg, 0.187 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3-dihydro-2H-benzimidazole -2-one (63.3 mg, 0.243 mmol), DMSO (2 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis (triphenylphosphine) palladium (II) chloride (10.51 mg, .0. The title compound was prepared in the same manner as described in Example 74 using 015 mmol)). 35 mg (40%) of the final product was recovered. LCMS ES (M + H) = 472.4 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.55 (d, J = 6.4 Hz, 6H), 2.13 (s, 3H), 2. 22 (s, 3H), 4.41 (d, J = 4.8 Hz, 2H), 5.30 (quin, J = 6.6 Hz, 1H), 5.91 (s, 1H), 7.07 ( d, J = 8.3 Hz, 1H), 7.86 (s, 1H), 7.92 (dd, J = 8.3, 1.8 Hz, 1H), 8.10 (s, 1H), 8. 30-8.41 (m, 1H), 8.98 (t, J = 4.8 Hz, 1H), 10.82 (s, 1H), 10.89 (s, 1H). 11.58 (s, 1H).

Example 81
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [6- (4-methyl-1-piperazinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (70 mg, 0.187 mmol), 1-methyl-4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyridinyl Piperazine (73.8 mg, 0.243 mmol), DMSO (2 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis (triphenylphosphine) palladium (II) chloride (10.51 mg, 0.015 mmol) Was used to prepare the title compound in the same manner as described in Example 74. 12 mg (13%) of the final product was recovered. LCMS ES (M + H) = 515.1 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.53 (d, J = 6.4 Hz, 6H), 2.13 (s, 3H), 2. 23 (m, 6H), 2.37-2.46 (m, 4H), 3.56-3.69 (m, 4H), 4.40 (d, J = 4.6 Hz, 2H), 5. 30 (quin, J = 6.7 Hz, 1H), 5.91 (s, 1H), 6.99 (d, J = 9.1 Hz, 1H), 8.10 (s, 1H), 8.32 ( s, 1H), 8.38 (dd, J = 9.1, 2.5 Hz, 1H), 8.91 (br.s., 1H), 9.03 (d, J = 2.3 Hz, 1H) .

Example 82
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [6- (4-methyl-1-piperazinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (70 mg, 0.187 mmol), 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine ( 73.6 mg, 0.243 mmol), 1,2-dimethoxyethane (DME) (3 mL), water (1 mL) sodium carbonate (0.281 mL, 0.562 mmol), and bis (triphenylphosphine) palladium (II) chloride. (12.23 mg, 0.015 mmol) was used to prepare the title compound in the same manner as described in Example 74, where the reaction time was 3 Was minute. The crude product was purified by column chromatography _{(eluent: 0~15% (9: 1MeOH /} NH 4 OH) / DCM gradient) of was purified by.
The product was dried under high vacuum and 58 mg (59%) was recovered. LCMS ES (M + H) = 514.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.51-1.58 (m, 6H), 2.13 (s, 3H), 2.23 ( s, 6H), 2.24 (s, 3H), 2.47 (m, 4H), 3.24-3.30 (m, 4H), 4.41 (d, J = 0.05 Hz, 2H) 5.30 (quin, J = 6.63 Hz, 1H), 5.90 (s, 1H), 7.07 (d, J = 9.09 Hz, 2H), 8.06 (s, 1H), 8 .15 (d, J = 8.84 Hz, 2H), 8.30 (s, 1H), 8.92 (t, J = 4.80 Hz, 1H), 11.55 (s, 1H).

Example 83
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -6- [6- (4-morpholinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide (70 mg, 0.180 mmol), [6- (4-morpholinyl) -3-pyridinyl] boronic acid (48.8 mg, 0.235 mmol), DMSO (2.0 mL), carbonic acid The title compound is the same as described in Example 74 using sodium (0.271 mL, 0.541 mmol), and bis (triphenylphosphine) palladium (II) chloride (10.13 mg, 0.014 mmol). Prepared by method, where the reaction time was 8 hours. The mixture was filtered and the residue was washed with DMSO.
The crude product in DMSO, reverse phase HPLC (mobile phase: 25~60% _{H 2} O in CAN, 0.1% TFA) and purified by. The resulting TFA product salt was neutralized with saturated NaHCO ₃ solution, filtered, washed with water and dried under high vacuum to give 24 mg (25%) of product. LCMS ES (M + H) = 516.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ
ppm 1.50 (d, J = 6.57 Hz, 6H), 2.12 (s, 3H), 2.25 (s, 3H), 2.42 (s, 3H), 3.54-3.63 (M, 4H), 3.73 (m, 4H), 4.39 (d, J = 4.80 Hz, 2H), 5.14-5.29 (m, 1H), 5.89 (s, 1H) ), 6.97 (d, J = 8.84 Hz, 1H), 7.63 (s, 1H), 8.37 (dd, J = 9.09, 2.53 Hz, 1H), 8.68 (t , J = 4.93 Hz, 1H), 8.98 (d, J = 2.27 Hz, 1H), 11.51 (s, 1H).

Example 84
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinylamino) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (50 mg, 0.134 mmol), 4-pyridinamine (12.59 mg, 0.134 mmol), cesium carbonate (131 mg, 0.401 mmol), 1,4-dioxane (2 mL), palladium acetate (II ) (1.501 mg, 6.69 μmol) and BINAP (8.33 mg, 0.013 mmol) were used to prepare the title compound in the same manner as described in Example 74, where the reaction time was 2 hours. 29 mg (50%) of the final product was recovered. LCMS ES (M + H) = 432.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.45-1.59 (d, J = 6.8 Hz, 6H), 2.14 (s, 3H ), 2.23 (s, 3H), 4.36 (d, J = 5.0 Hz, 2H), 5.16 (m, 1H), 5.91 (s, 1H), 7.09 (s, 1H), 7.9 (d, J = 6.1 Hz, 2H), 8.12 (s, 1H) 8.49 (d, J = 6.6 Hz, 2H), 8.74 (t, J = 5 .1 Hz, 1H), 10.58 (s, 1H), 11.58 (s, 1H).

Example 85
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-[(2-oxo-2,3-dihydro- 1H-benzimidazol-5-yl) amino] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-amino-1,3-dihydro-2H-benzimidazol-2-one (33.5 mg, 0.225 mmol), cesium carbonate (92 mg, 0.281 mmol) , N, N-dimethylacetamide (DMA) (2 mL), palladium (II) acetate (2.52 mg, 0.011 mmol) and xanthophos (10.83 mg, 0.019 mmol) were used to prepare the title compound in the Examples Prepared in the same way as described in 74, in which the reaction temperature was 150 ° C. and the reaction time was 8 hours. 25 mg (27%) of the final product was recovered. LCMS ES (M + H) = 487.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.50-1.61 (m, 6H), 2.13 (s, 3H), 2.23 ( s, 3H), 4.38 (d, J = 5.0 Hz, 2H), 5.20 (quin, J = 6.6 Hz, 1H), 5.90 (s, 1H), 6.79-6. 91 (m, 2H), 8.04 (d, J = 8.3 Hz, 1H), 8.26-8.33 (m, 2H), 8.84 (t, J = 5.0 Hz, 1H), 11.50 (s, 1H).

Example 86
6-{[4- (Aminocarbonyl) phenyl] amino} -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide (70 mg, 0.180 mmol), 4-aminobenzamide (29.5 mg, 0.217 mmol), cesium carbonate (88 mg, 0.271 mmol), N, N-dimethylacetamide (DMA) (1.5 mL), palladium (II) acetate (2.431 mg, 10.83 μmol) and xanthophos (10.44 mg, 0.018 mmol) were used to prepare the title compound as described in Example 74. The reaction temperature was 150 ° C. and the reaction time was 1 hour. 12 mg (14%) of the final product was recovered. LCMS ES (M + H) = 488.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.48 (d, J = 6.4 Hz, 6H), 2.13 (s, 3H), 2. 23 (s, 3H), 2.32 (s, 3H), 4.35 (d, J = 4.8 Hz, 2H), 4.99 (quin, J = 6.8 Hz, 1H), 5.89 ( s, 1H), 6.65 (s, 1H), 7.15 (br.s., 1H), 7.75-7.82 (m, 1H), 7.84-7.96 (m, 4H) ), 8.56 (t, J = 4.9 Hz, 1H), 9.77 (s, 1H).

Example 87
1- (1,1-Dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- [6- (4- Methyl-1-piperazinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-1- (1,1-dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (70 mg, 0.174 mmol), 1-methyl-4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) -2-pyridinyl] piperazine (68.7 mg, 0.226 mmol), DME (3 mL), water (1.00 mL), sodium carbonate (0.261 mL, 0.523 mmol) and PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (11.38mg, 0.014mmol) using the title compound was prepared in the same manner as described in example 74, where the reaction time is 40 minutes Was Tsu. The crude product was purified by column chromatography (eluent: 0-15% (9: gradient of _{1 MeOH / NH 4 OH) /} DCM) was purified by. The final product was recovered as a solid 41 mg (43%). LCMS ES (M + H) = 543.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.78 (s, 9H), 2.12 (s, 3H), 2.24 (m, 7H) , 2.38 (s, 3H), 2.39-2.49 (m, 4H), 3.34 (s, 3H), 4.38 (m, 2H), 5.88 (s, 1H), 6.98 (d, J = 9.09 Hz, 1H), 7.59 (s, 1H), 8.93-8.97 (m, 1H), 11.49-11.57 (m, 1H), 11.53 (s, 1H), 11.53 (s, 1H).

Example 88
1- (1,1-Dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- (2-oxo-2 , 3-Dihydro-1H-benzimidazol-5-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-1- (1,1-dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (70 mg, 0.174 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3- Dihydro-2H-benzimidazol-2-one (58.9 mg, 0.226 mmol), DME (3 mL), water (1.00 mL), sodium carbonate (0.261 mL, 0.523 mmol) and PdCl ₂ (dppf)- CH ₂ Cl ₂ adduct (11.38mg, 0.014mmol) using the title compound was prepared in the same manner as described in example 74, where the reaction time It was 0 minutes. The crude product was purified by column chromatography (eluent: 0-15% (9: gradient of _{1 MeOH / NH 4 OH) /} DCM) was purified by. The final product was recovered as a solid 24 mg (27%). LCMS ES (M + H) = 500.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.77 (m, 9H), 2.12 (s, 3H), 2.24 (s, 3H) , 2.40 (s, 3H), 4.38 (d, J = 4.55 Hz, 2H), 5.89 (s, 1H), 7.06 (d, J = 8.08 Hz, 1H), 7 .59 (s, 1H), 7.72-7.86 (m, 2H), 8.73 (br.s., 2H), 10.74-10.92 (m, 1H), 11.53 ( br.s., 1H).

Example 89
1- (1,1-Dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- [6- (4- Morpholinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-1- (1,1-dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (70 mg, 0.174 mmol), [6- (4-morpholinyl) -3-pyridinyl] boronic acid (47.1 mg, 0.226 mmol), DME (3 mL), water (1.00 mL), sodium carbonate (0.261 mL, 0.523 mmol) and PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (11.38 mg, 0.014 mmol) were used to give the title compound in the Examples Prepared in the same way as described in 74, where the reaction time was 40 minutes. The crude product was purified by column chromatography (eluent: 0-15% (9: gradient of _{1 MeOH / NH 4 OH) /} DCM) was purified by. The final product was recovered as a solid 61 mg (65%). LCMS ES (M + H) = 530.0 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.78 (s, 9H), 2.12 (s, 3H), 2.24 (s, 3H) 2.38 (s, 3H), 3.52-3.64 (m, 4H), 3.68-3.80 (m, 4H), 4.38 (d, J = 0.05 Hz, 2H) , 5.88 (s, 1H), 6.99 (d, J = 9.09 Hz, 1H), 7.61 (s, 1H), 8.34 (dd, J = 8.84, 2.53 Hz, 1H), 8.68 (t, J = 0.05 Hz, 1H), 8.97 (d, J = 2.27 Hz, 1H), 11.53 (s, 1H).

Example 90
6- (2,1,3-Benzoxadiazol-5-yl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl- 1- (1-Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide (70 mg, 0.180 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,1,3- Benzoxadiazole (57.7 mg, 0.235 mmol), DMSO (2 mL), sodium carbonate (0.271 mL, 0.541 mmol), and bis (triphenylphosphine) palladium (II) chloride (12.67 mg, 0.25 mmol). The title compound was prepared in the same manner as described in Example 74, where the reaction time was 8 hours. 17 mg (20%) of the final product was recovered. LCMS LCMS ES (M + H) = 472.4 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.53 (d, J = 6.8 Hz, 6H), 2.12 (s, 3H), 2 .27 (s, 3H) 4.42 (d, J = 4.8 Hz, 2H) 5.32 (quin, J = 6.6 Hz, 1H), 5.90 (s, 1H), 8.00 (s , 1H), 8.23 (d, J = 9.4 Hz, 1H), 8.54-8.64 (m, 1H), 8.79 (t, J = 4.7 Hz, 1H), 8.91. (S, 1H), 11.54 (br.s., 1H).

Example 91
6- (2-Amino-6-quinazolinyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl ) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide (70 mg, 0.180 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,1,3- Benzoxadiazole (57.7 mg, 0.235 mmol), DMSO (2 mL), sodium carbonate (0.271 mL, 0.541 mmol), and bis (triphenylphosphine) palladium (II) chloride (12.67 mg, 0.25 mmol). The title compound was prepared in the same manner as described in Example 74, where the reaction time was 8 hours. 28 mg (31%) of the final product was recovered. LCMS ES (M + H) = 497.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.52 (d, J = 6.8 Hz, 6H), 2.12 (s, 3H), 2. 26 (s, 3H), 4.41 (d, J = 5.0 Hz, 2H) 5.30 (quin, J = 6.6 Hz, 1H), 5.89 (s, 1H), 7.16 (br .S., 2H), 7.56 (d, J = 9.1 Hz, 1H), 7.78 (s, 1H) 8.60 (dd, J = 8.8, 2.0 Hz, 1H), 8 .69 (d, J = 1.8 Hz, 1H), 8.76 (t, J = 4.9 Hz, 1H), 9.28 (s, 1H), 11.53 (s, 1H).

Example 92
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- {4-[(methylamino) sulfonyl] phenyl} -1- (1 -Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide (80 mg, 0.21 mmol), {4-[(methylamino) sulfonyl] phenyl} boronic acid (66.5 mg, 0.31 mmol) and bis (triphenylphosphine) palladium (II ) Chloride (8.4 mg, 0.01 mmol) was suspended in DME / water (4 mL, 3: 1) and stirred for 10 minutes at room temperature under nitrogen. Sodium bicarbonate (52 mg, 0.62 mmol) was added and the heterogeneous mixture was irradiated (microwave) at 150 ° C. for 30 minutes. After cooling to room temperature, water was added to the black mixture and the contents were vacuum filtered. The crude product was dissolved in DCM / MeOH (1: 1) and pre-adsorbed on silica gel. The product was purified by silica gel chromatography (eluent: DCM / MeOH / NH4OH, gradient 0-90: 10: 1). The collected light beige solid was suspended in EtOH, sonicated and filtered. The solid was then air dried for 15 minutes and then dried overnight in a vacuum oven. 77 mg (70%) of the final product was recovered. LCMS
E-S (M + H) = 523.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.54 (br.s., 1H) 8.78 (t, J = 0.05 Hz, 1H) 43 (m, J = 8.59 Hz, 2H) 7.93 (m, J = 8.59 Hz, 2H) 7.78 (s, 1H) 7.58 (br.s., 1H) 5.89 (s , 1H) 5.29 (quin, J = 6.63 Hz, 1H) 4.40 (d, J = 4.80 Hz, 2H) 2.46 (d, J = 1.26 Hz, 6H) 2.25 (s , 3H) 2.12 (s, 3H) 1.52 (s, 3H) 1.51 (s, 3H).

Example 93
6- [4- (Acetylamino) phenyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl ) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide (80 mg, 0.21 mmol), [4- (acetylamino) phenyl] boronic acid (55.4 mg, 0.31 mmol), bis (triphenylphosphine) palladium (II) chloride ( 8.4 mg, 0.01 mmol), DME / water (4 mL, 3: 1) and sodium bicarbonate (52 mg, 0.62 mmol) were used to prepare the title compound in the same manner as described in Example 93. Prepared. The crude product was dissolved in DCM / MeOH (1: 1) and pre-adsorbed on silica gel. The product was purified by silica gel chromatography (eluent: DCM / MeOH / NH4OH, gradient 0-80: 20: 2). The collected solid was suspended in EtOH / EtOAc (1: 1), sonicated and filtered. After further washing with hexane, the solid was then air dried for 15 minutes and then dried overnight in a vacuum oven. 70 mg (69%) of the final product was recovered. LCMS ES (M + H) = 487.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.53 (br.s., 1H) 10.16 (s, 1H) 8.73 (t, J = 5.05 Hz, 1H) 8.17 (m, J = 8.84 Hz, 2H) 7.74 (m, J = 8.84 Hz, 2H) 7.64 (s, 1H) 5.89 (s, 1H) ) 5.25 (quin, J = 6.69 Hz, 1H) 4.39 (d, J = 4.80 Hz, 2H) 2.43 (s, 3H) 2.25 (s, 3H) 2.12 (s) , 3H) 2.09 (s, 3H) 1.51 (s, 3H) 1.49 (s, 3H).

Example 94
6- [4- (Aminocarbonyl) phenyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (80 mg, 0.21 mmol), [4- (aminocarbonyl) phenyl] boronic acid (52.9 mg, 0.31 mmol), bis (triphenylphosphine) palladium (II) chloride (8.7 mg, The title compound was prepared in the same manner as described in Example 93 using 0.01 mmol), DME / water (4 mL, 3: 1) and sodium bicarbonate (54 mg, 0.62 mmol). The crude product was dissolved in DCM / MeOH (1: 1) and pre-adsorbed on silica gel. The product was purified by silica gel chromatography _{(eluent: DCM / MeOH / NH 4 OH} ( gradient 0 to 90: 10: 1)) was purified by. The collected solid was suspended in EtOH, sonicated and filtered. After further washing with EtOH / DCM, the solid was then air dried for 15 minutes and then dried in a vacuum oven overnight. 70 mg (69%) of the final product was recovered. LCMS ES (M + H) = 459.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.58 (s, 1H) 9.00 (t, J = 4.93 Hz, 1H) 8.41 ( s, 1H) 8.36 (s, 1H) 8.34 (s, 1H) 8.24 (s, 1H) 8.13 (s, 1H) 8.06 (s, 1H) 8.04 (s, 1H) 7.51 (s, 1H) 5.91 (s, 1H) 5.37 (quin, J = 6.69 Hz, 1H) 4.42 (d, J = 4.80 Hz, 2H) 2.23 ( s, 3H) 2.13 (s, 3H) 1.56 (s, 3H) 1.55 (s, 3H).

Example 95
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-{[2- (2-pyridinylamino) ethyl] amino } -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide (80 mg, 0.21 mmol) and (2-aminoethyl) 2-pyridinylamine (88 mg, 0.64 mmol) were suspended in 2 mL NMP and irradiated (microwave) as follows: 180 30 ° C., 30 minutes at 200 ° C., 30 minutes at 220 ° C., 30 minutes at 230 ° C., then 1 hour at 240 ° C. After cooling to room temperature, some solvent was removed in vacuo and the residue was purified by silica gel chromatography (eluent: DCM / MeOH / NH ₄ OH, gradient 0-90: 10: 1). The collected solid was separated between water and EtOAc / toluene (1: 1) and then extracted twice with DCM / isopropanol.
The combined organic layers were washed with water, dried over MgSO ₄ , filtered and concentrated under vacuum to give a dark brown oil. After drying overnight under vacuum, the residue was again purified by silica gel chromatography (eluent: DCM / MeOH / NH ₄ OH, (gradient 0-90: 10: 1)).
The collected solid was suspended in EtOH, sonicated and filtered. After further washing with EtOH / DCM, it was filtered and dried in a vacuum oven for 2 days. 47 mg (45%) of the final product was recovered. LCMS ES (M + H) = 475.0 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.56 (br.s., 1H) 8.47 (t, J = 0.05 Hz, 1H) 7 .97 (dd, J = 4.93, 1.14 Hz, 1H) 7.85 (s, 1H) 7.32-7.39 (m, 2H) 6.65 (s, 1H) 6.61 (t , J = 5.43 Hz, 1H) 6.46-6.51 (m, 2H) 5.89 (s, 1H) 4.97 (quin, J = 6.69 Hz, 1H) 4.32 (d, J = 5.05 Hz, 2H) 3.49 (dt, J = 15.28, 5.62 Hz, 4H) 2.21 (s, 3H) 2.13 (s, 3H) 1.44 (s, 3H) 1 .43 (s, 3H).

Example 96
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (7-oxo-1,5,6,7 -Tetrahydro-1,8-naphthyridin-3-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Bromo-3,4-dihydro-1,8-naphthyridin-2 (1H) -one (200 mg, 0.881 mmol) (J. Med. Chem. 2003; 46; 9; 1627-1635), bis (pinacolato ) Diboron (268 mg, 1.057 mmol), Pd (dppf) (35.7 mg, 0.044 mmol) and potassium acetate (259 mg, 2.64 mmol) were suspended in 1,4-dioxane (8 mL) and heated. Stir at 100 ° C. for 1 hour. After cooling to room temperature, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (329 mg, 0.881 mmol), bis (triphenylphosphine) palladium (II) chloride (71.9 mg, 0.088 mmol) and sodium bicarbonate (222 mg, 2.64 mmol) Followed by DME (5 mL) and water (3 mL). The reaction mixture was irradiated (microwave) at 120 ° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Na2SO4. The contents are purified directly by silica gel chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ) and the desired product is evaporated from warm EtOAc / MeOH (1: 9), precipitated, then gray solid Got as. 55 mg (13%) of product was recovered. LCMS ES (M + H) = 486.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (br.s., 1H), 10.74 (s, 1H), 8.99 (d) , J = 2.27 Hz, 1H), 8.93 (t, J = 4.93 Hz, 1H), 8.44 (d, J = 1.77 Hz, 1H), 8.37 (s, 1H), 8 .16 (s, 1H), 5.91 (s, 1H), 5.29-5.40 (m, 1H), 4.42 (d, J = 0.05 Hz, 2H), 3.04 (t , J = 7.58 Hz, 2H), 2.53-2.62 (m, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.54 (d, 6H).

Example 97
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- {6-[(methylamino) sulfonyl] -3-pyridinyl} -1- (1- Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

5-Bromo-N-methyl-2-pyridinesulfonamide (225 mg, 0.896 mmol), bis (pinacolato) diboron (296 mg, 1.165 mmol), Pd (dppf) (35.7 mg, 0.044 mmol) and potassium acetate (264 mg, 2.69 mmol) was suspended in 1,4-dioxane (8 mL) and stirred with heating at 100 ° C. for 1 hour. After cooling to room temperature, 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide (368 mg, 0.986 mmol), bis (triphenylphosphine) palladium (II) chloride (73.2 mg, 0.090 mmol) and sodium bicarbonate (226 mg, 2.69 mmol) Followed by DME (5 mL) and water (3 mL). The reaction mixture was irradiated (microwave) at 120 ° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Na ₂ SO ₄ . The contents are purified directly by silica gel chromatography (eluent: 15% MeOH / CH ₂ Cl ₂ ) and the desired product is evaporated from warm EtOAc / MeOH (1: 9), precipitated, then gray solid Got as. The product was purified again by silica gel chromatography (eluent: 5% MeOH / CH ₂ Cl ₂ ) to give the final product as a white solid, 83 mg (18%). LCMS ES (M + H) = 510.0 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.59 (br.s., 1H), 9.56 (d, J = 1.52 Hz, 1H) , 8.96 (s, 1H), 8.86 (dd, J = 8.34, 2.27 Hz, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.12 (D, J = 8.34 Hz, 1H), 7.85 (br.s., 1H), 5.91 (s, 1H), 5.27-5.46 (m, 1H), 4.43 ( d, J = 4.80 Hz, 2H), 2.60 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 1.56 (d, 6H).

Intermediate 17
5-Bromo-N-methyl-2-pyridinesulfonamide

5-Bromo-2-pyridinesulfonyl chloride (500 mg, 1.949 mmol) was added to pyridine (0.315 mL, 3.90 mmol), methylamine (0.975 mL, 1.949 mmol, 2M in THF) and CH ₂ Cl ₂ ( 2 mL) in a 0 ° C. solution. The reaction mixture was stirred at room temperature for 1 hour and then quenched with brine. The contents were extracted with DCM, dried, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluent: 50%, EtOAC / CH ₂ Cl ₂ ). The product was recovered as a clear oil, 225 mg (75%). LCMS ES (M + H) = 251.1. ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.77 (s, 1H), 8.07 (dd, J = 8.34, 2.27 Hz, 1H), 7.92 (d, J = 8. 34 Hz, 1H), 5.45 (d, J = 0.05 Hz, 1H), 2.76 (d, 3H).

Intermediate 18
1-{[4- (Methyloxy) phenyl] methyl} -1H-pyrazol-5-amine

Hydrazine hydrate (12.82 g 400 mmol) was added dropwise to a cooled (<20 ° C.) solution of 2-propenenitrile (21.76 g 410 mmol) and ethanol (200 mL). After stirring for 16 hours, the reaction mixture was cooled in an ice-water bath and 4- (methyloxy) benzaldehyde (53.8 g 395 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness. The residue was dissolved in n-butanol (200 mL), sodium hydroxide (1 g 25.00 mmol) was added and the mixture was heated at 120 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure to 50% volume, poured into 300 mL water, and then extracted with Et ₂ O (2 × 200 mL). The combined ether phase was extracted with 1N HCl (3 × 100 mL). Combined HCl extracts were combined and cooled in an ice / water bath. Next, 6N NaOH was added until basic (pH> 12). The contents were extracted with Et ₂ O (4 × 100 mL), washed with water, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: 0-50% EtOAc: Hex). 8.94 g (11%) of the final product was recovered. ¹ H NMR (400 MHz, chloroform-d) δ ppm 3.79 (s, 3H), 5.14 (s, 2H), 5.55 (d, J = 1.77 Hz, 1H), 6.81-6 .94 (m, 2H), 7.12 (d, J = 8.84 Hz, 2H), 7.31 (d, J = 2.02 Hz, 1H).

Intermediate 19
1-Cyclobutyl-3-methyl-1H-pyrazol-5-amine

(2Z) -3-Amino-2-butenenitrile (1.339 g, 16.31 mmol) and cyclobutylhydrazine HCl (2 g, 16.31 mmol) were added to ethanol (20 mL) and heated at 75 ° C. for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The crude residue was suspended in saturated NaHCO ₃ (30 mL) and EtOAc (50 mL) and stirred for 10 minutes. The phases were separated and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined EtOAc extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated under vacuum.
The crude residue was purified by silica gel chromatography (eluent: 0-5% EtOAc: DCM, then gradient to 100% EtOAc). 0.4 g (16%) of the final product was recovered. LCMS ES (M + H) =: 152.0. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.67-2.00 (m, 2H) 2.21 (s, 3H) 2.32-2.43 (m, 2H) 2.69 (ddd, J = 10.55, 9.41, 2.53 Hz, 2H) 3.26-3.55 (brs, 2H) 4.48-4.59 (m, 1H) 5.36 (s, 1H)

Intermediate 20
1-Cyclopentyl-3-methyl-1H-pyrazol-5-amine

Cyclopentylhydrazine hydrochloride (2 g, 14.64 mmol), (2Z) -3-amino-2-butenenitrile (1.202 g, 14.64 mmol) and ethanol (20 mL) were used to give the title compound as intermediate 19 Was prepared in the same manner as described for. 0.57 g (24%) of the final product was recovered. LCMS ES (M + H) = 166.0. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.60-1.69 (m, 2H), 1.86-1.95 (m, 2H), 1.99-2.09 (m, 4H) 2.19 (s, 3H), 3.46 (br.s., 2H), 4.38 (quin, J = 7.89 Hz, 1H), 5.36 (s, 1H).

Intermediate 21
1- (Phenylmethyl) -1H-pyrazol-5-amine

A solution of hydrazine hydrate (14.55 mL, 300 mmol) and ethanol (75 mL) was cooled in an ice-water bath, and then 2-propenenitrile (15.3 g, 288 mmol) was added dropwise. After stirring at room temperature for 2 hours, benzaldehyde (31.8 g, 300 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2 days. The solvent was removed under reduced pressure. The crude oil was cooled in an ice / water bath followed by the dropwise addition of n-BuONa solution (6.9 g Na (300 mmol) in n-butanol (300 mL)). The reaction mixture was heated at reflux for 1 hour and then cooled to room temperature. The contents were poured into 300 mL of water and then extracted with Et ₂ O (2 × 200 mL). The ether phase was extracted with 1N HCl (3 × 100 mL). The combined HCl extracts were combined and cooled in an ice / water bath followed by 6N NaOH until basic (pH> 12). The mixture was extracted with Et ₂ O (4 × 100 mL), washed with water, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 0-50% EtOAc: Hex). 6.96 g (14%) of final product was recovered. LCMS ES (M + H) = 174.0. ¹ H NMR (400 MHz, chloroform-d) δ ppm 3.39 (br.s., 2H), 5.23 (s, 2H), 5.59 (d, J = 1.77 Hz, 1H), 7. 17 (d, J = 6.82 Hz, 2H), 7.28-7.37 (m, 4H)

Intermediate 22
1,1-Dimethylethyl 2- (tetrahydro-2H-pyran-4-yl) hydrazinecarboxylate

Tetrahydro-4H-pyran-4-one (9.69 g, 97 mmol) is added to a solution of 1,1-dimethylethylhydrazinecarboxylate (14.07 g, 106 mmol) in methanol (100 mL) and stirred at room temperature for 3 hours. did. The solvent was removed under vacuum and the crude residue was suspended in acetic acid (140 mL). Next, sodium cyanoborohydride (6.69 g, 106 mmol) was added in portions over 3 minutes. The contents were stirred at room temperature for 60 hours. The solvent was removed under vacuum and the crude residue was suspended in DCM (100 mL). The reaction mixture is diluted with 6N
The pH was adjusted to 7 with NaOH. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with saturated NaHCO ₃ and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give the product as a solid 18.4 g (88%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.22 (m, 2H), 1.39 (s, 9H), 1.43-1.48 (m, 1H), 1.59-1. 69 (m, 2H), 2.82-2.98 (m, 1H), 3.20-3.32 (m, 2H), 3.80 (d, J = 11.62 Hz, 2H), 4. 36 (br.s., 1H), 8.07-8.34 (m, 1H).

Intermediate 23
Tetrahydro-2H-pyran-4-ylhydrazine

1,1-Dimethylethyl 2- (tetrahydro-2H-pyran-4-yl) hydrazinecarboxylate was added to 1,4-dioxane (10 mL) followed by hydrochloric acid (4 M in 1,4-dioxane, 10 mL, 329 mmol). ) Was added. The reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was filtered to give the product as a solid 1.02 g (72%). ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.45 (qd, J = 11.79, 4.29 Hz, 2H), 1.81-2.01 (m, 2H), 3.00-3. 19 (m, 1H), 3.20-3.35 (m, 2H), 3.78-3.97 (m, 2H), 6.5-9.5 (brm, 3H).

Intermediate 24
3-Methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-5-amine

(2Z) -3-Amino-2-butenenitrile (0.538 g, 6.55 mmol), tetrahydro-2H-pyran-4-ylhydrazine (1 g, 6.55 mmol) and triethylamine (0.913 mL, 6.55 mmol) Was added to ethanol (300 mL) and the reaction mixture was stirred at 75 ° C. for 16 h. The solvent was removed under vacuum and the crude material was suspended in EtOAc. The organic phase was washed with water and then with brine. The organic layer was then dried over MgSO ₄ , filtered and concentrated under vacuum. Half of the crude material was purified by reverse phase HPLC (mobile phase: 0-30% ACN / H ₂ O, 0.1% TFA) to give 380 mg of the desired product. The other half of the crude material was purified by silica gel chromatography (eluent: 0% to 100% EtOAc: Hex, then 0% to 20% MeOH: DCM). An additional 300 mg of the desired product was obtained (overall yield: 57%). LCMS ES (M + H) = 182.0. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.78 (dd, 2H), 1.94 (qd, J = 12.13, 4.55 Hz, 2H), 2.19 (s, 3H), 3 .30-3.46 (m, 2H), 3.99 (dd, J = 11.49, 4.17 Hz, 2H), 4.49 (m, J = 11.65, 11.65, 4.11) , 3.92 Hz, 1H), 5.53 (s, 1H).

Intermediate 25
6-Methyl-1- (phenylmethyl) -1H-pyrazolo [3,4-b] pyridin-4-ol

1- (phenylmethyl) -1H-pyrazol-4-amine (6.25 g, 36.1 mmol), ethyl 3-oxobutanoate (4.70 g, 36.1 mmol), acetic acid (0.2 mL, 3.49 mmol) And a mixture of benzene (50 mL) was refluxed for 16 hours (using a Dean-Stark trap). The solvent was removed under reduced pressure and the crude residue was purified by silica gel chromatography (eluent; 0-60% EtOAc: Hex). The recovered product (7.35 g, 25.8 mmol) was then dissolved in 10 mL of Dowtherm A and this solution was added dropwise to 10 mL of refluxing Dowtherm A. After refluxing for an additional 20 minutes, the reaction mixture was cooled to room temperature and 20 mL of petroleum ether was added. After stirring at room temperature for 16 hours, the solid product was filtered and dried under high vacuum. The final product was recovered 6.23 g (72%). LCMS ES (M + H) = 240.0. ¹ H NMR (400 MHz, MeOD) δ ppm 4.89 (s, 3H), 5.59 (s, 2H), 6.17 (br.s., 1H), 7.17 (d, J = 6. 82 Hz, 2H), 7.25-7.37 (m, 3H), 8.05 (s, 1H).

Intermediate 26
4-Bromo-6-methyl-1- (phenylmethyl) -1H-pyrazolo [3,4-b] pyridine

Phosphorus oxybromide (5.31 g, 18.54 mmol) was converted to 6-methyl-1- (phenylmethyl) -1H-pyrazolo [3,4-b] pyridin-4-ol (3.08 g, 12.87 mmol). And added to a suspension of toluene (25 mL). The contents were heated to reflux for 1 hour and 10 mL of DMF was added during the process. The solvent was removed under reduced pressure. The crude residue was suspended in 30 mL water with ice. The contents were adjusted to pH = 10 by adding saturated NaHCO ₃ . The solid product was filtered and dried under high vacuum. 3.55 g (91%) of the final product was recovered. LCMS ES (M + H) = 302.1 / 304.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.61 (s, 3H), 5.65 (s, 2H), 7.16-7.35 (m, 5H), 7.48 (s, 1H), 8.12 s, 1H).

Intermediate 27
6-Methyl-1- (phenylmethyl) -1H-pyrazolo [3,4-b] pyridine-4-carbonitrile

4-Bromo-6-methyl-1- (phenylmethyl) -1H-pyrazolo [3,4-b] pyridine (3.45 g, 11.42 mmol), dicyanozinc (1.542 g, 13.13 mmol), tris ( A mixture of dibenzylideneacetone) dipalladium (0) (0.523 g, 0.571 mmol), SPhos (0.562 g, 1.370 mmol), DMF (49 mL), and water (0.5 mL) was added with nitrogen for 10 minutes. I was degassed. The reaction mixture was heated at 120 ° C. for 2 hours and then cooled to room temperature. The contents were concentrated to 50% volume, then 50 mL of 1N NaOH and 50 mL of EtOAc were added. The solid was collected by filtration. The phases were separated and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined EtOAc extracts were washed with water (3 × 50 mL), brine (50 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. 3.69 g of crude product containing SPhos reagent (˜30-40%) was recovered and used without further purification. LCMS ES (M + H) = 249.1. ¹ H NMR (400 MHz, chloroform-d) δ ppm 2.77 (s, 3H), 5.73 (s, 2H), 7.08-7.44 (m, 6H), 8.16 (s, 1H )

Intermediate 28
6-Methyl-1- (phenylmethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

6-Methyl-1- (phenylmethyl) -1H-pyrazolo [3,4-b] pyridine-4-carbonitrile (1 g), sodium hydroxide (0.805 g, 20.14 mmol), ethanol (25 mL) and water (10 mL) was heated at reflux for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was suspended in water (50 mL) and acidified by the dropwise addition of 6N HCl. The solid product was collected by filtration and dissolved in 100 mL of EtOAc. The solution was dried over MgSO ₄ , filtered and concentrated under vacuum. 0.730 g of final product was obtained. LCMS ES (M + H) = 267.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.71 (s, 3H), 5.70 (s, 2H), 7.15-7.37 (m, 5H), 7.63 (s, 1H), 8.33 (s, 1H), 13.86 (s, 1H).

Intermediate 29
Ethyl 4-cyclopropyl-2,4-dioxobutanoate

Sodium metal (2.411 g, 105 mmol) was dissolved in ethanol (50 mL). The solution was heated at reflux, followed by the dropwise addition of a mixture of 1-cyclopropylethanone (8.4 g, 100 mmol) and diethyl oxalate (14.59 g, 100 mmol) over 30 minutes. The reaction mixture was heated at reflux for an additional 2 hours and then cooled to room temperature over 2 days. The contents were diluted with water (200 mL) and acidified by adding 6N HCl dropwise. The contents were extracted with EtOAc (3 × 75 mL), washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The final product was recovered 14.3 g (74%). LCMS ES (M + H) = 184.8 ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.03 (d, J = 7.83 Hz, 2H) 1.13-1.19 (m, 2H) 1 .31 (t, J = 7.07 Hz, 3H) 1.81-1.90 (m, 1H) 4.29 (q, J = 7.16 Hz, 2H) 6.43 (s, 1H).

Intermediate 30
Ethyl 6-cyclopropyl-1-{[4- (methyloxy) phenyl] methyl} -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

1-{[4- (methyloxy) phenyl] methyl} -1H-pyrazol-5-amine (3 g, 14.76 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (2.72 g, 14.76 mmol) and benzene (50 mL) were heated at 63 ° C. for 16 h. The solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography (eluent: 0-25% EtOAc: Hex) to give 2.56 g of the desired cyclized product and 1.71 g of an acyclic adduct. The non-cyclized adduct was dissolved in 25 mL AcOH and heated to reflux for 16 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (eluent: 0-25% EtOAc: Hex) to give an additional 1.15 g of the desired cyclized product (combined yield = 71%). LCMS ES (M + H) = 352.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.07-1.13 (m, 4H) 1.38 (t, J = 7.07 Hz, 3H) 2.39 (s, 1H) 3.67 (S, 3H) 4.41 (q, J = 7.07 Hz, 2H) 5.51 (s, 2H) 6.84 (d, J = 8.84 Hz, 2H) 7.21 (d, J = 8 .59 Hz, 2H) 7.64 (s, 1H) 8.23 (s, 1H).

Intermediate 31
Ethyl 6-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

In a 20 mL microwave vial, add ethyl 6-cyclopropyl-1-{[4- (methyloxy) phenyl] methyl} -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (2.05 g, 5. 83 mmol), trifluoroacetic acid (6.74 mL, 88 mmol) and anisole (1.912 mL, 17.50 mmol) were combined. The reaction vessel was sealed and irradiated (microwave) at 100 ° C. for 5 minutes. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was diluted with water (20 mL) and then diluted to basic with saturated NaHCO ₃ . The contents were extracted with DCM (4 × 20 mL). The combined organic layers were washed with water, brine, dried over MgSO ₄ , filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluent: 0-20% EtOAc: Hex). 1.06 g (79%) of the final product was obtained. LCMS ES (M + H) = 232.2. ¹ H
NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.95-1.21 (m, 4H) 1.41 (t, J = 7.07 Hz, 3H) 2.33-2.46 (m, 1H) 4 .44 (q, J = 7.07 Hz, 2H) 7.67 (s, 1H) 8.26 (d, J = 1.26 Hz, 1H) 13.75 (s, 1H).

Intermediate 32
Ethyl 1-amino-6-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 6-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (200 mg, 0.865 mmol) is dissolved in N-methyl-2-pyrrolidone (NMP) (8 mL) followed by potassium. Tert-butoxide (116 mg, 1.038 mmol) was added. After stirring for 20 minutes, O-{[4- (methyloxy) phenyl] carbonyl} hydroxylamine 1-[(aminooxy) carbonyl] -4- (methyloxy) benzene (289 mg, 1.730 mmol) was added and the mixture Was stirred at room temperature for 16 hours. The contents were diluted with EtOAc and then washed with brine and saturated NaHCO ₃ .
The organic phase was dried over MgSO ₄ , filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluent: 0-50% EtOAc). 106 mg (50%) of the final product was recovered. LCMS ES (M + H) = 274.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.00-1.14 (m, 4H), 1.41 (t, J = 7.07 Hz, 3H), 2.34-2.47 (m , 1H), 4.44 (q, J = 7.07 Hz, 2H), 6.39 (s, 2H), 7.64 (s, 1H), 8.09 (s, 1H).

Intermediate 33
Ethyl 6-cyclopropyl-3-methyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 4-cyclopropyl-2,4-dioxobutanoate (700 mg, 3.76 mmol), 3-methyl-1- (1-methylethyl) -1H-pyrazol-5-amine (523 mg, 3.76 mmol) And a solution of benzene (20 mL) was heated at 65 ° C. for 6 hours and then cooled to room temperature for 2 days. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (eluent: 0-25% EtOAc: Hex). 0.77 g (71%) of final product was recovered. LCMS ES (M + H) = 288.0. ¹ H NMR (400 MHz, chloroform-d) · δ ppm 1.04-1.11 (m, 2H), 1.13-1.20 (m, 4H), 1.47 (t, J = 7.20 Hz) 6H), 1.55 (d, J = 6.82 Hz, 12H), 2.16-2.25 (m, 2H), 2.68 (s, 6H), 4.49 (q, J = 7). .07 Hz, 4H), 5.20 (spt, J = 6.78 Hz, 2H), 7.41 (s, 1H).

Intermediate 34
Ethyl 1-cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

1-cyclobutyl-3-methyl-1H-pyrazol-5-amine (400 mg, 2.65 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (487 mg, 2.65 mmol) and benzene (50 mL) Was used to prepare the title compound in the same manner as described for Intermediate 33, where the reaction time was 4 hours. 0.556 g (70%) of the final product was recovered. LCMS ES (M + H) = 300.6 ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.02-1.22 (m, 4H) 1.47 (t, J = 7.07 Hz, 3H) 1 .80-2.01 (m, 2H) 2.15-2.28 (m, 1H) 2.38-2.51 (m, 2H) 2.70 (s, 3H) 2.82 (td, J = 9.85, 2.53 Hz, 2H) 4.49 (q, J = 7.07 Hz, 2H) 5.32-5.57 (m, 1H) 7.41 (s, 1H).

Intermediate 35
Ethyl 1-cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

1-cyclopentyl-3-methyl-1H-pyrazol-5-amine (570 mg, 3.45 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (635 mg, 3.45 mmol), and benzene (50 mL) ) Was used to prepare the title compound in the same manner as described for Intermediate 33, where the reaction time was 4 hours. The crude product was purified by silica gel chromatography (eluent: 0-10% EtOAc: Hex). 0.740 g (68%) of the final product was recovered. LCMS ES (M + H) = 314.3 ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.04-1.21 (m, 4H) 1.47 (t, J = 7.20 Hz, 3H) 1 .73 (br.s., 2H) 2.00 (d, J = 2.78 Hz, 2H) 2.08-2.16 (m, 4H) 2.21 (s, 1H) 2.67 (s, 3H) 4.49 (q, J = 7.16 Hz, 2H) 5.32 (t, J = 7.83 Hz, 1H) 7.40 (s, 1H).

Intermediate 36
Ethyl 6-cyclopropyl-1- (1,1-dimethylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 4-cyclopropyl-2,4-dioxobutanoate (481 mg, 2.61 mmol), 1- (1,1-dimethylethyl) -3-methyl-1H-pyrazol-5-amine (400 mg, 2. 61 mmol), and toluene (20 mL) were used to prepare the title compound in the same manner as described for Intermediate 33, where the reaction time was 3 hours. The crude product was purified by silica gel chromatography (eluent: 0-10% EtOAc: Hex). 0.24 g (30%) of the final product was recovered. LCMS ES (M + H) = 302.5. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.02-1.23 (m, 4H) 1.47 (t, J = 7.20 Hz, 3H) 1.79 (s, 9H) 2.19 ( s, 1H) 2.66 (s, 3H) 4.49 (q, J = 7.07 Hz, 2H) 7.44 (s, 1H).

Intermediate 37
Ethyl 6-cyclopropyl-1- (1-cyclopropylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

1- (1-Cyclopropylethyl) -3-methyl-1H-pyrazol-5-amine (500 mg, 3.03 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (557 mg, 3.03 mmol) ) Was suspended in toluene (10 mL) and heated at 70 ° C. for 16 h. The solvent was removed in vacuo and the crude residue was purified by silica gel chromatography (eluent: 0-10% EtOAc: Hex gradient). The final product was recovered as 0.722 g (76%) solid. LCMS ES (M + H) = 314.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.17-0.32 (m, 2H), 0.39 (m, J = 9.69, 4) .82, 4.82, 4.67 Hz, 1H), 0.51-0.62 (m, 1H), 0.94-1.11 (m, 4H), 1.28-1.41 (m, 4H), 1.58 (d, J = 6.82 Hz, 3H), 2.30-2.38 (m, 1H), 2.56 (s, 3H), 4.19 (dq, J = 9. 44, 6.87 Hz, 1H), 4.43 (q, J = 7.07 Hz, 2H), 7.48 (s, 1H)

Intermediate 38
Ethyl 1-cyclohexyl-6-cyclopropyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

1- (1-cyclohexyl) -3-methyl-1H-pyrazol-5-amine (500 mg, 2.79 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (514 mg, 2.79 mmol). Using, the title compound was prepared in the same manner as described for Intermediate 37. The final product was recovered as 0.827 g (91%) solid. LCMS ES (M + H) = 328.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.01-1.10 (m, 3H), 1.20-1.30 (m, 1H), 1.37 (t, J = 7.07 Hz, 3H), 1.41-1.52 (m, 2H), 1.70 (d, 1H), 1.79-1.98 (m, 6H), 2.30-2.38 (m, 1H), 2.54 (s, 3H), 4.42 (q, J = 7.07 Hz, 2H), 4.60-4.74 (m, 1H), 7.44 (s, 1H).

Intermediate 39
Ethyl 6-cyclopropyl-3-methyl-1- (1-methyl-4-piperidinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

3-Methyl-1- (1-methyl-4-piperidinyl) -1H-pyrazol-5-amine (500 mg, 2.57 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (474 mg, 2 .57 mmol) was suspended in toluene (10 mL) and heated at 70 ° C. for 5 hours. The solvent was removed in vacuo and the crude residue was purified by silica gel chromatography (eluent: 0-10% MeOH: DCM gradient). The final product was recovered as 0.722 g (76%) solid. LCMS ES (M + H) = 343.1 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.03-1.11 (m, 4H), 1.38 (t, J = 7.07 Hz, 3H ), 1.83 (d, J = 6.06 Hz, 2H), 2.12-2.22 (m, 4H), 2.27 (s, 3H), 2.35 (m, J = 7.83). 7.83, 5.05, 4.80 Hz, 1H), 2.54 (s, 3H), 2.94 (d, J = 6.57 Hz, 2H), 4.42 (q, J = 7. 16 Hz, 2H), 4.57-4.73 (m, 1H), 7.46 (s, 1H).

Intermediate 40
Ethyl 6-cyclopropyl-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

3-Methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-5-amine (380 mg, 2.097 mmol), ethyl (3Z) -4-cyclopropyl-4-hydroxy-2-oxo A mixture of -3-butenoate (386 mg, 2.097 mmol) and acetic acid (50 mL) was heated at 117 ° C. for 2 hours. The solvent was removed under vacuum and the crude residue was purified by silica gel chromatography (eluent: 0-25% EtOAc: Hex). The desired product was recovered as 300 mg (43%) solid. LCMS ES (M + H) = 330.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.00-1.12 (m, 4H), 1.37 (t, J = 7.20 Hz, 3H ), 1.82 (dd, J = 12.51, 2.40 Hz, 2H), 2.16 (qd, J = 12.21, 4.55 Hz, 2H), 2.29-2.42 (m, 1H), 2.54 (s, 3H), 3.47-3.60 (m, 2H), 3.99 (dd, J = 11.37, 3.79 Hz, 2H), 4.42 (q, J = 7.24 Hz, 2H), 4.92 (tt, J = 11.59, 4.20 Hz, 1H), 7.46 (s, 1H).

Intermediate 41
Ethyl 6-cyclopropyl-1- [2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 6-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (125 mg, 0.541 mmol) was dissolved in DMF (10 mL) followed by potassium tert-butoxide (79 mg, 0.703 mmol). ) Was added. After stirring for 15 minutes, 1,1-dimethylethyl (2-bromoethyl) carbamate (121 mg, 0.541 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness. The crude residue was diluted with water (50 mL) and acidified with acetic acid. The contents were extracted with DCM (4 × 50 mL). The combined organic layers were washed with water, brine, dried over MgSO ₄ , filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography (eluent: 0-50% EtOAc: Hex). 0.114 g (56%) of the final product was obtained. LCMS ES (M + H) = 375.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.04-1.14 (m, 4H), 1.15-1.20 (m, 2H), 1.27 (s, 7H), 1. 41 (t, J = 7.07 Hz, 3H), 2.36-2.45 (m, 1H), 3.31-3.41 (m, 3H), 4.36-4.50 (m, 5H) ), 6.84 (t, J = 5.81 Hz, 1H), 7.65 (s, 1H), 8.24 (s, 3H).

Intermediate 42
Ethyl 6-cyclopropyl-3-methyl-1- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

3-methyl-1- (4-pyridinyl) -1H-pyrazol-5-amine (310 mg, 1.780 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (328 mg, 1.780 mmol), The title compound was prepared in the same manner as described for Intermediate 30 using benzene (50 mL), and acetic acid (25 mL). The final product was recovered 3.71 (71% overall). LCMS ES (M + H) = 323.5 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.15-1.22 (m, 4H), 1.41 (t, J = 7.07 Hz, 3H ), 2.64-2.69 (m, 4H), 4.47 (q, J = 7.07 Hz, 2H), 7.74 (s, 1H), 8.27-8.36 (m, 2H) ), 8.66-8.71 (m, 2H).

Intermediate 43
6-Cyclopropyl-1-ethyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

To a solution of ethyl 6-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (200 mg, 0.865 mmol) in DMF (10 mL) was added sodium hydride (29.1 mg, 1.211 mmol). ) Was carefully added. After stirring for 15 minutes, iodoethane (0.077 mL, 0.951 mmol) was added and the mixture was stirred at room temperature for 2 hours. Sodium hydroxide (1 mL, 1.000 mmol) was added and the mixture was stirred at room temperature for 1 hour. The contents were concentrated under vacuum. The crude residue was diluted with water (50 mL) and acidified with acetic acid. The contents were then extracted with DCM (4 × 50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluent: hexane to 100% EtOAc, then DCM to 20% MeOH: DCM). The final product was recovered 90 mg (45%). ^{LCMS E-S (M + H} ) = 232.1 1 H NMR (400MHz, DMSO-d 6) δ ppm 1.06-1.17 (m, 4H) 1.41 (t, J = 7.33Hz, 3H) 2.35-2.45 (m, 1H) 4.34-4.57 (m, 2H) 7.62 (s, 1H) 8.24 (s, 1H) 13.83 (br.s., 1H ).
Regiochemical assignment supported by 2D HNMR.

Intermediate 44
6-Cyclopropyl-1-propyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 6-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (200 mg, 0.865 mmol), sodium hydride (29.1 mg, 1.211 mmol), DMF (10 mL), 1- The title compound was prepared in the same manner as described for Intermediate 43 using iodopropane (162 mg, 0.951 mmol), and NaOH (1 mL). The crude product was purified by silica gel chromatography (eluent: 0-10% MeOH: DCM) to give the final product as a solid 90 mg (42%). Regiochemical assignment supported by 2D HNMR. LCMS ES (M + H) = 246.0 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.83 (brs, 1H), 8.24 (s, 1H), 7.62 (s, 1H) , 4.26 (t, 2H, J = 7.2 Hz), 2.37-2.40 (m, 2H), 1.83-1.89 (m, 2H), 1.07-1.11 ( m, 4H), 0.77 (t, 3H, J = 7.2 Hz).

Intermediate 45
1-amino-6-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

To a solution of ethyl 1-amino-6-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (100 mg, 0.406 mmol) in ethanol (10 mL) was added sodium hydroxide (1 mL, 0 .406 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was diluted with EtOAc (30 mL) and water (20 mL). The reaction mixture was acidified to pH 3 with citric acid. The phases were separated and the aqueous phase was extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with water, dried over MgSO ₄ , filtered and concentrated under vacuum. 0.075 g (84%) of the final product was recovered. LCMS ES (M + H) = 219.5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.00-1.13 (m, 4H), 2.27-2.45 (m, 1H), 6.36 (s, 2H), 7. 60 (s, 1H), 8.06 (s, 1H), 13.81 (br.s., 1H).

Intermediate 46
6-Cyclopropyl-3-methyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

A solution of ethyl 6-cyclopropyl-3-methyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (200 mg, 0.696 mmol) in ethanol (5 mL) To was added sodium hydroxide (2.088 mL, 2.088 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was diluted with water (30 mL) and then acidified with acetic acid. The contents were extracted with DCM (3 × 30 mL). The combined organic layers were washed with water, brine, dried over MgSO ₄ , filtered and concentrated under vacuum. 0.17 g (94%) of the final product was obtained. LCMS ES (M + H) = 260.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.97-1.12 (m, 4H) 1.44 (d, J = 6.57 Hz, 6H) 2.27-2.38 (m, 1H ) 2.55 (s, 3H) 5.07 (quin, J = 6.69 Hz, 1H) 7.43 (s, 1H) 13.30-14.08 (m, 1H).

Intermediate 47
6-Cyclopropyl-1- [2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 6-cyclopropyl-1- [2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (110 mg, The title compound was prepared in the same manner as described for intermediate 46 using 0.294 mmol), sodium hydroxide (1 mL, 0.294 mmol), and ethanol (10 mL), where stirring The time was 16 hours. 0.060 g (59%) of the final product was recovered. LCMS ES (M + H) = 347.1 ¹ H
NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.06-1.13 (m, 4H) 1.27 (s, 9H) 2.33-2.43 (m, 1H) 3.37 (q, J = 5.81 Hz, 2H) 4.44 (t, J = 5.94 Hz, 2H) 6.84 (t, J = 5.81 Hz, 1H) 7.62 (s, 5H) 8.24 (s, 1H ).

Intermediate 48
1-cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 1-cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (550 mg, 1.837 mmol), sodium hydroxide (3 mL, 3.00 mmol), and The title compound was prepared in the same manner as described for intermediate 46 using ethanol (30 mL), where the stirring time was 1 hour. 0.490 g (98%) of final product was recovered. LCMS ES (M + H) = 272.5 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.03-1.10 (m, 4H), 1.80-1.91 (m, 2H), 2.26-2.43 (m, 3H), 2.58 (s, 3H), 2.59-2.71 (m, 2H), 5.35 (dq, J = 8.59, 8.42 Hz) , 1H), 7.44 (s, 1H), 13.73 (br.s., 1H).

Intermediate 49
1-Cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 1-cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (740 mg, 2.361 mmol), sodium hydroxide (4 mL, 4.00 mmol), and The title compound was prepared in the same manner as described for intermediate 46 using ethanol (30 mL), where the stirring time was 1 hour. The final product was recovered 0.530 g (79%). LCMS ES (M + H) = 286.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.96-1.12 (m, 4H) 1.52-1.74 (m, 2H) 82-2.13 (m, 6H) 2.26-2.37 (m, 1H) 2.55 (s, 3H) 5.17-5.30 (m, 1H) 7.43 (s, 1H) 13.70 (br.s., 1H).

Intermediate 50
6-Cyclopropyl-1- (1,1-dimethylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 6-cyclopropyl-1- (1,1-dimethylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (240 mg, 0.796 mmol), sodium hydroxide (4 mL (4.00 mmol), and ethanol (30 mL) were used to prepare the title compound in the same manner as described for Intermediate 46, where the stirring time was 1 hour. 0.210 g (96%) of the final product was recovered. LCMS ES (M + H) = 274.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.05 (m, 4H) 1.70 (s, 9H) 2.33 (m, 1H) 2.51 (s, 3H) 7.46 (s , 1H) 13.70 (br.s., 1H).

Intermediate 51
6-Cyclopropyl-3-methyl-1- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

  Ethyl 6-cyclopropyl-1- (4-pyridinyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (240 mg, 0.796 mmol), sodium hydroxide (4 mL, 4. The title compound was prepared in the same manner as described for intermediate 46 using 00 mmol), and ethanol (30 mL), where the stirring time was 1 hour. 0.210 g (89%) of the final product was recovered. LCMS ES (M + H) = 295.3.

Intermediate 52
6-Cyclopropyl-1- (1-cyclopropylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

To a solution of ethyl 6-cyclopropyl-1- (1-cyclopropylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (720 mg, 2.297 mmol) in EtOH (10 mL). , Sodium hydroxide (6.89 mL, 6.89 mmol) was added and the mixture was heated at 70 ° C. for 1 h. The solvent was removed under vacuum and the residue was dissolved in 20 mL water. The contents were acidified with acetic acid and extracted with EtOAc (4 × 30 mL).
The combined organic extracts were washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The final product was recovered as 0.560 g (85%) solid. LCMS ES (M + H) = 286.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.15-0.33 (m, 2H), 0.38 (dq, J = 9.57, 4 .89 Hz, 1H), 0.50-0.65 (m, 1H), 0.90-1.10 (m, 4H), 1.27-1.42 (m, 1H), 1.57 (d , J = 6.82 Hz, 3H), 2.23-2.36 (m, 1H), 2.57 (s, 3H), 4.18 (dq, J = 9.32, 6.83 Hz, 1H) 7.44 (s, 1H), 12.79 (br.s., 1H).

Intermediate 53
1-Cyclohexyl-6-cyclopropyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 6-cyclopropyl-1- (1-cyclohexyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (820 mg, 2.5 mmol) and sodium hydroxide (7.51 mL, The title compound was prepared in the same manner as described for Intermediate 52 using 7.51 mmol). The final product was recovered as 0.660 g (88%) solid. LCMS ES (M + H) = 300.4 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.01-1.11 (m, 4H), 1.16-1.31 (m, 1H), 1.36-1.55 (m, 2H), 1.70 (d, J = 12.38 Hz, 1H), 1.80-1.98 (m, 6H), 2.32 (m, J = 7 .80, 7.80, 5.05, 4.86 Hz, 1H), 2.55 (s, 3H), 4.60-4.73 (m, 1H), 7.40 (s, 1H), 13 .71 (br.s., 1H).

Intermediate 54
6-Cyclopropyl-3-methyl-1- (1-methyl-4-piperidinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 6-cyclopropyl-3-methyl-1- (1-methyl-4-piperidinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (620 mg, 1.811 mmol) in EtOH (10 mL) ) Was added sodium hydroxide (5.43 mL, 5.43 mmol) and the mixture was heated at 70 ° C. for 1 h. The solvent was removed under vacuum and the residue was dissolved in 20 mL water. The contents were acidified with acetic acid and extracted with EtOAc (4 × 30 mL). The combined organic extracts were washed with water, brine, dried over MgSO ₄ , filtered, and concentrated in vacuo to give a small amount of product. The aqueous phase is concentrated in vacuo and the crude residue is purified by reverse phase HPLC (eluent: 0% ACN / H ₂ O, 0.1% TFA to 45% ACN / H ₂ O, 0.1% TFA). Purified. The isolated solid product was concentrated from toluene to give 510 mg (90%) of the final product. LCMS ES (M + H) = 315.2. ¹ H
NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.08 (d, J = 6.57 Hz, 4H), 2.10 (d, J = 13.14 Hz, 2H), 2.30-2.42 (m , 3H), 2.55 (s, 3H), 2.77-2.92 (m, 3H), 3.30 (br.s., 2H), 3.57 (d, J = 12.13 Hz, 2H), 4.98 (m, J = 11.78, 11.78, 3.85, 3.66 Hz, 1H), 7.46 (s, 1H), 9.87 (br.s., 1H) .

Intermediate 55
6-Cyclopropyl-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

EtOH solution of ethyl 6-cyclopropyl-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (300 mg, 0.911 mmol) To (30 mL) was added sodium hydroxide (1.82 mL, 1.82 mmol) and the mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum and the residue was dissolved in 20 mL water. The contents were acidified with acetic acid and extracted with EtOAc (4 × 30 mL). The combined organic extracts were washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give 265 mg (97%) of the final product. LCMS ES (M + H) = 302.4 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.02-1.09 (m, 4H), 1.81 (dd, J = 12.38, 2 .27 Hz, 2H), 2.15 (qd, J = 12.55, 4.42 Hz, 2H), 2.28-2.37 (m, 1H), 2.54 (s, 3H), 3.46. -3.60 (m, 2H), 3.89-4.02 (m, 2H), 4.91 (m, J = 11.56, 11.56, 4.17, 4.04 Hz, 1H), 7.42 (s, 1H), 13.73 (br.s., 1H).

Intermediate 56
(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl 6-cyclopropyl-1- [2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl ] -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

To a solution of DMSO (10 mL) was added 6-cyclopropyl-1- [2-({[(1,1-dimethylethyl) oxy] carbonyl} amino) ethyl] -1H-pyrazolo [3,4-b] pyridine- 4-carboxylic acid (270 mg, 0.779 mmol), 3- (aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (178 mg, 1.169 mmol), and 1-hydroxy-7-azabenzotriazole ( 212 mg, 1.559 mmol) was added sequentially and the mixture was stirred at room temperature for 10 minutes. Then EDC (299 mg, 1.559 mmol) and N-methylmorpholine (0.343 mL, 3.12 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The contents were diluted with water (25 mL) and stirred for 10 minutes. The solid product was filtered, dried and 0.290 g (98%) was recovered. LCMS ES (M + H) = 381.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.00-1.15 (m, 4H), 1.30 (s, 9H), 2.13 (s, 3H), 2.18-2. 32 (m, 4H), 4.36 (d, J = 4.80 Hz, 2H), 4.42 (t, J = 5.81 Hz, 2H), 5.90 (s, 1H), 6.85 ( t, J = 5.56 Hz, 1H), 7.44 (s, 1H), 8.22 (s, 2H), 8.73 (t, J = 4.67 Hz, 1H), 11.57 (br. s., 1H).

Example 98
1- (2-Aminoethyl) -6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1H-pyrazolo [3,4-b Pyridine-4-carboxamide

1,1-dimethylethyl {2- [6-cyclopropyl-4-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] amino in DCM (15 mL) } Carbonyl) -1H-pyrazolo [3,4-b] pyridin-1-yl] ethyl} carbamate (260 mg, 0.541 mmol) was added trifluoroacetic acid (3 mL, 38.9 mmol) and the mixture Was stirred at room temperature for 2 hours. The contents were concentrated in vacuo and the crude residue was purified by reverse phase HPLC (mobile phase: 10-70% ACN in H ₂ O, 0.1% NH ₄ OH). The final product was 0.170 g (89%). It was collected. LCMS ES (M + H) = 353.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.07 (d, J = 6.32 Hz, 4H), 2.13 (s, 3H), 2. 21 (s, 4H), 3.00 (t, J = 6.19 Hz, 2H), 4.29-4.47 (m, 4H), 5.90 (s, 1H,) 7.43 (s, 1H), 8.22 (s, 1H), 8.75 (t, 1H).

Example 99
6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- {2-[(methylsulfonyl) amino] ethyl} -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

1- (2-Aminoethyl) -6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1H-pyrazolo in pyridine (2 mL) To a solution of [3,4-b] pyridine-4-carboxamide (120 mg, 0.315 mmol) was added methanesulfonyl chloride (0.025 mL, 0.315 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated under vacuum. The crude product was purified by reverse phase HPLC to give a solid (25 mg). This solid was suspended in MeOH (1 mL) and treated with 4N HCl (1 mL). The solvent was removed under reduced pressure to give the final product as a solid, recovering 15 mg (9%). LCMS ES (M + H) = 459.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.02-1.15 (m, 4H), 2.13 (s, 3H), 2.22 (s, 3H), 2.23-2. 31 (m, 1H), 2.82 (s, 3H), 3.45 (q, 2H), 4.36 (d, J = 0.05 Hz, 2H), 4.49 (t, J = 6. 44 Hz, 2H), 5.90 (s, 1H), 7.19 (s, 1H), 7.47 (s, 1H), 8.25 (s, 1H), 8.76 (t, J = 4 .93 Hz, 1H), 11.56 (s, 1H).

Example 100
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6-methyl-1- (phenylmethyl) -1H-pyrazolo [3,4-b] pyridine- 4-carboxamide

6-Methyl-1- (phenylmethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (200 mg, 0.748 mmol), 3- (aminomethyl) -4,6-dimethyl-2 ( 1H) -pyridinone (142 mg, 0.935 mmol), 1-hydroxy-7-azabenzotriazole (204 mg, 1.497 mmol), DMSO (10 mL), EDC (287 mg, 1.497 mmol), and N-methylmorpholine (0 The title compound was prepared in the same manner as described for Intermediate 56 using .329 mL, 2.99 mmol). 0.25 g (83%) of final product was recovered. LCMS ES (M + H) = 402.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.93-1.12 (m, 4H), 1.42 (d, J = 6.82 Hz, 6H), 2.12 (s, 3H), 2.22 (s, 4H), 2.36 (s, 3H), 4.34 (d, J = 4.80 Hz, 2H), 4.90-5.11 (m, 1H), 5.87 ( s, 1H), 6.99 (s, 1H), 8.58 (s, 1H), 11.51 (s, 1H.

Example 101
6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1-ethyl-1H-pyrazolo [3,4-b] pyridine-4- Carboxamide

6-Cyclopropyl-1-ethyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (91 mg, 0.394 mmol), 3- (aminomethyl) -4,6-dimethyl-2 (1H) -Pyridinone (75 mg, 0.493 mmol), 1-hydroxy-7-azabenzotriazole (107 mg, 0.788 mmol), DMSO (10 mL), EDC (151 mg, 0.788 mmol), and N-methylmorpholine (0.173 mL) , 1.577 mmol) was used to prepare the title compound in the same manner as described for Intermediate 56. 0.090 g (63%) of the final product was recovered. LCMS ES (M + H) = 366.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.07 (d, J = 6.32 Hz, 4H), 1.39 (t, J = 7.20 Hz) , 3H), 2.13 (s, 3H), 2.19-2.32 (m, 4H), 4.36 (d, J = 4.80 Hz, 2H), 4.42 (q, J = 7) .07 Hz, 2H), 5.90 (s, 1H), 7.43 (s, 1H), 8.21 (s, 1H), 8.75 (t, J = 4.67 Hz, 1H), 11. 57 (br.s., 1H).

Example 102
6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1-propyl-1H-pyrazolo [3,4-b] pyridine-4- Carboxamide

6-Cyclopropyl-1-propyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (90 mg, 0.368 mmol), 3- (aminomethyl) -4,6-dimethyl-2 (1H) -Pyridinone (70 mg, 0.460 mmol), 1-hydroxy-7-azabenzotriazole (100 mg, 0.736 mmol), DMSO (10 mL), EDC (141 mg, 0.736 mmol), and N-methylmorpholine (0.162 mL) , 1.472 mmol) was used to prepare the title compound in the same manner as described for Intermediate 56. 0.118 g (84%) of the final product was recovered. LCMS ES (M + H) = 380.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.78 (t, 3H), 0.99-1.16 (m, 4H), 1.85 (d, J = 7.33 Hz, 2H), 2.13 (s, 3H), 2.22 (s, 4H), 4.25-4.43 (m, 4H), 5.90 (s, 1H), 7.43 (s, 1H), 8 .21 (s, 1H), 8.75 (s, 1H), 11.57 (s, 1H).

Example 103
6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide

6-Cyclopropyl-1- (2-methylpropyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (80 mg, 0.309 mmol), 3- (aminomethyl) -4,6-dimethyl -2 (1H) -pyridinone (70.4 mg, 0.463 mmol), 1-hydroxy-7-azabenzotriazole (84 mg, 0.617 mmol), DMSO (10 mL), EDC (118 mg, 0.617 mmol), and N The title compound was prepared in the same way as described for intermediate 56 using methylmorpholine (0.136 mL, 1.234 mmol). 0.123 g (100%) of the final product was recovered. LCMS ES (M + H) = 394.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.93-1.12 (m, 4H), 1.42 (d, J = 6.82 Hz, 6H ), 2.12 (s, 3H), 2.22 (s, 4H), 2.36 (s, 3H), 4.34 (d, J = 4.80 Hz, 2H), 4.90-5. 11 (m, 1H), 5.87 (s, 1H), 6.99 (s, 1H), 8.58 (s, 1H), 11.51 (s, 1H).

Example 104
1-amino-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1H-pyrazolo [3,4-b] pyridine-4- Carboxamide

1-amino-6-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (73 mg, 0.335 mmol), 3- (aminomethyl) -4,6-dimethyl-2 (1H) -Pyridinone (76 mg, 0.502 mmol), 1-hydroxy-7-azabenzotriazole (91 mg, 0.669 mmol), DMSO (10 mL), EDC (128 mg, 0.669 mmol), and N-methylmorpholine (0.147 mL) , 1.338 mmol) was used to prepare the title compound in the same manner as described for Intermediate 56. The aqueous phase was extracted with EtOAc (5 × 30 mL). The combined EtOAc extracts were dried over MgSO _4, filtered, and concentrated in vacuo. 0.068 g (58%) of the final product was recovered. LCMS ES (M + H) = 353.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.99-1.14 (m, 4H), 2.13 (s, 3H), 2.22 (s, 4H), 4.35 (d, J = 4.80 Hz, 2H), 5.90 (s, 1H), 6.31 (s, 2H), 7.41 (s, 1H), 8.04 (s, 1H), 8.74 (s) , 1H), 11.58 (br.s., 1H).

Example 105
1-cyclobutyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [3,4-b] Pyridine-4-carboxamide

1-cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (164 mg, 0.604 mmol), 3- (aminomethyl) -4,6-dimethyl- 2 (1H) -pyridinone (129 mg, 0.846 mmol), 1-hydroxy-7-azabenzotriazole (165 mg, 1.209 mmol), EDC (232 mg, 1.209 mmol), N-methylmorpholine (0.266 mL, 2 .418 mmol), and DMSO (10 mL) were used to prepare the title compound in the same manner as described for Intermediate 56. 0.240 g (98%) of the final product was recovered. LCMS ES (M + H) = 406.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.03 (d, J = 6.06 Hz, 4H), 1.85 (dd, J = 9.35, 5.05 Hz, 3H), 2.12 (S, 4H), 2.16-2.28 (m, 6H), 2.30-2.44 (m, 7H), 2.63 (d, J = 19.96 Hz, 3H), 4.34 (D, J = 4.29 Hz, 2H), 5.31 (t, J = 8.34 Hz, 1H), 5.87 (s, 1H), 7.01 (s, 1H), 8.59 (br .S., 1H), 11.52 (br.s., 1H).

Example 106
1-cyclopentyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [3,4-b] Pyridine-4-carboxamide

1-cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (160 mg, 0.561 mmol), 3- (aminomethyl) -4,6-dimethyl- 2 (1H) -pyridinone (119 mg, 0.785 mmol), 1-hydroxy-7-azabenzotriazole (153 mg, 1.121 mmol), EDC (215 mg, 1.121 mmol), N-methylmorpholine (0.247 mL, 2 The title compound was prepared in the same manner as described for Intermediate 56 using .243 mmol) and DMSO (10 mL). 0.205 g (87%) of the final product was recovered. LCMS ES (M + H) = 420.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.03 (d, J = 6.06 Hz, 4H), 1.85 (dd, J = 9.35, 5.05 Hz, 3H), 2.12 (S, 4H), 2.16-2.28 (m, 6H), 2.30-2.44 (m, 7H), 2.63 (d, J = 19.96 Hz, 3H), 4.34 (D, J = 4.29 Hz, 2H), 5.31 (t, J = 8.34 Hz, 1H), 5.87 (s, 1H), 7.01 (s, 1H), 8.59 (br .S., 1H), 11.52 (br.s., 1H).

Example 107
6-Cyclopropyl-1- (1,1-dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-Cyclopropyl-1- (1,1-dimethylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (210 mg, 0.768 mmol), 3- (aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (158 mg, 1.037 mmol), 1-hydroxy-7-azabenzotriazole (209 mg, 1.537 mmol), EDC (295 mg, 1.537 mmol), N-methyl The title compound was prepared in the same manner as described for Intermediate 56 using morpholine (0.338 mL, 3.07 mmol), and DMSO (10 mL). 0.280 g (89%) of the final product was recovered. LCMS ES (M + H) = 408.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.02 (dddd, 4H), 1.69 (m, 9H), 2.12 (s, 3H), 2.22 (m, 4H), 2 .33 (s, 3H), 4.34 (d, J = 4.80 Hz, 2H), 5.87 (s, 1H), 7.04 (s, 1H), 8.55 (m, 1H), 11.51 (s, 1H).

Example 108
6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (4-pyridinyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide

6-Cyclopropyl-3-methyl-1- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (89 mg, 0.302 mmol), 3- (aminomethyl) -4 6-Dimethyl-2 (1H) -pyridinone (69.0 mg, 0.454 mmol), 1-hydroxy-7-azabenzotriazole (82 mg, 0.605 mmol), DMSO (20 mL), EDC (116 mg, 0.605 mmol) , And N-methylmorpholine (0.133 mL, 1.210 mmol) were used to prepare the title compound in the same manner as described for Intermediate 56. 0.110 g (80%) of the final product was recovered. LCMS ES (M + H) = 429.1 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.15 (br.s., 4H), 2.13 (br.s., 3H), 2. 25 (br.s., 4H), 3.34 (br.s., 3H), 4.37 (br.s., 2H), 5.89 (br.s., 1H), 7.30 ( br.s., 1H), 8.33 (br.s., 2H), 8.67 (br.s., 3H), 11.54 (br.s., 1H).

Example 109
6-cyclopropyl-1- (1-cyclopropylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide

6-Cyclopropyl-1- (1-cyclopropylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (186 mg, 0.652 mmol), 3- (aminomethyl)- 4,6-Dimethyl-2 (1H) -pyridinone (160 mg, 0.847 mmol), 1-hydroxy-7-azabenzotriazole (177 mg, 1.304 mmol), EDC (250 mg, 1.304 mmol) and N-methylmorpholine (0.287 mL, 2.61 mmol) was dissolved in DMSO (10 mL) and stirred at room temperature for 3 days. The reaction mixture was diluted with water (25 mL), stirred and filtered. The product was dried and recovered as a solid 0.200 g (73%). LCMS ES (M + H) = 420.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.14-0.30 (m, 2H), 0.32-0.43 (m, 1H), 0.48-0.64 (m, 1H) ), 0.89-1.11 (m, 4H), 1.22-1.43 (m, 1H), 1.55 (d, J = 6.82 Hz, 3H), 2.11 (s, 3H) ), 2.18-2.28 (m, 4H), 2.37 (s, 3H), 4.05-4.21 (m, 1H), 4.34 (d, J = 4.80 Hz, 2H) ), 5.87 (s, 1H), 6.99 (s, 1H), 8.59 (t, J = 4.67 Hz, 1H), 11.51 (br.s., 1H).

Example 110
1-cyclohexyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [3,4-b] Pyridine-4-carboxamide

6-cyclopropyl-1- (1-cyclohexyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (150 mg, 0.501 mmol), and 3- (aminomethyl) -4 The title compound was prepared in the same manner as described in Example 109, using 6-dimethyl-2 (1H) -pyridinone (123 mg, 0.651 mmol). The product was recovered as 0.190 g (87%) solid. LCMS ES (M + H) = 434.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.95-1.07 (m, 4H), 1.15-1.31 (m, 1H), 1.36-1.52 (m, 2H) ), 1.68 (br.s., 1H), 1.77-1.99 (m, 6H), 2.11 (s, 3H), 2.18-2.29 (m, 4H), 2 .35 (s, 3H), 4.33 (d, J = 4.80 Hz, 2H), 4.53-4.73 (m, 1H), 5.87 (s, 1H), 6.96 (s , 1H), 8.58 (t, J = 4.93 Hz, 1H), 11.51 (s, 1H).

Example 111
6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methyl-4-piperidinyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

6-cyclopropyl-3-methyl-1- (1-methyl-4-piperidinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (150 mg, 0.477 mmol), 3- (aminomethyl ) -4,6-dimethyl-2 (1H) -pyridinone (117 mg, 0.620 mmol), 1-hydroxy-7-azabenzotriazole (130 mg, 0.954 mmol), EDC (183 mg, 0.954 mmol) and N- Methylmorpholine (0.210 mL, 1.909 mmol) was suspended in DMSO (10 mL) and stirred at room temperature for 16 hours. Then 25 mL of water was added and stirred for 10 minutes, then extracted with EtOAc (5 ×). The organic layer was concentrated under vacuum to give 20 mg of product. The aqueous phase was concentrated under vacuum and the crude residue was purified by reverse phase HPLC (mobile phase: 10-60% ACN in H ₂ O, 0.1% NH ₄ OH) to give additional product. The final product was recovered as 0.100 g (47%) solid. LCMS ES (M + H) = 449.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.97-1.05 (m, 4H), 1.79 (d, J = 9.60 Hz, 2H), 2.11 (s, 3H), 2.15 (d, J = 8.34 Hz, 3H), 2.21 (s, 3H), 2.23-2.27 (m, 3H), 2.35 (s, 3H), 2.91 ( d, J = 8.08 Hz, 2H), 4.33 (d, J = 4.80 Hz, 2H), 4.49-4.72 (m, 1H), 5.86 (s, 1H), 6. 97 (s, 1H), 6.92-7.07 (m, 1H), 8.58 (t, J = 4.93 Hz, 1H), 11.50 (s, 1H).

Example 112
6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (tetrahydro-2H-pyran-4-yl)- 1H-pyrazolo [3,4-b] pyridine-4-carboxamide

6-cyclopropyl-3-methyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (150 mg, 0.498 mmol), and 3- The title compound was prepared in the same manner as described in Example 109 using (aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (98 mg, 0.647 mmol). The product was recovered as 0.170 g (78%) solid. LCMS ES (M + H) = 436.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ
ppm 0.95-1.14 (m, 4H), 1.79 (dd, J = 12.63, 2.27 Hz, 2H), 2.05-2.18 (m, 5H), 2.19- 2.27 (m, 4H), 2.36 (s, 3H), 3.53 (t, J = 11.12 Hz, 2H), 3.98 (dd, J = 11.49, 3.41 Hz, 2H) ), 4.33 (d, J = 4.80 Hz, 2H), 4.87 (m, J = 11.53, 11.53, 4.11, 3.92 Hz, 1H), 5.87 (s, 1H), 6.99 (s, 1H), 8.59 (t, J = 4.93 Hz, 1H), 11.51 (s, 1H).

Intermediate 57
Ethyl 1- (1-methylethyl) -6-propyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

To a solution of ethyl 2,4-dioxoheptanoate (446 mg, 2.397 mmol) in benzene (5 mL) was added 1- (1-methylethyl) -1H-pyrazol-5-amine (300 mg, 2.397 mmol). And the mixture was stirred at 62 ° C. for 18 hours. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (silica gel, 0-100% EtOAc / hexanes gradient) to give 370 mg (56%) of product.
LCMS ES (M + H) = 276.1. ¹ H NMR (400 MHz, chloroform-d) δ ppm 0.99-1.12 (m, 3H), 1.46-1.54 (m, 3H), 1.58-1.70 (m, 6H) , 1.82-1.96 (m, 2H), 2.91-3.02 (m, 2H), 4.51 (q, J = 7.2 Hz, 2H), 5.28-5.44 ( m, 1H), 7.58-7.68 (s, 1H), 8.27-8.40 (s, 1H)

Intermediate 58
1- (1-Methylethyl) -6-propyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

A solution of ethyl 1- (1-methylethyl) -6-propyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (180 mg, 0.654 mmol) in ethanol (5 mL) and THF (1 mL) To the mixture was added sodium hydroxide (1.090 mL, 3.27 mmol) and the mixture was stirred at 40 ° C. for 1 hour. Volatiles were removed under reduced pressure.
The aqueous phase was acidified to pH 3 with 1N aqueous HCl. The solid precipitate that formed was collected by filtration and dried under high vacuum to give 144 mg (89%) of product that was used in the next reaction without further purification. LCMS ES (M + H) = 248.1 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82-1.12 (m, 3H), 1.50 (d, J = 6.6 Hz, 6H) ), 1.78 (m, 2H), 2.80-3.11 (m, 2H), 5.09-5.38 (m, 1H), 7.47-7.72 (s, 1H), 8.18-8.46 (s, 1H), 13.82 (s, 1H).

Intermediate 60
Ethyl 4- [4- (methyloxy) phenyl] -2,4-dioxobutanoate

Using sodium metal (0.168 g, 7.32 mmol), 1- [4- (methyloxy) phenyl] ethanone (1 g, 6.66 mmol), and diethylethanedioate (0.903 mL, 6.66 mmol) The title compound was prepared in the same manner as Intermediate 29. The crude product was purified using column chromatography (0-100% EtOAc / hexanes) to give 0.95 g of product (57%). LCMS ES (M + H) = 250.9. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.43 (m, 3H), 3.91 (s, 3H), 4.41 (q, J = 6.65 Hz, 2H), 6.94-7 .12 (m, 3H), 8.01 (d, J = 8.59 Hz, 2H).

Intermediate 61
Ethyl 1- (1-methylethyl) -6- [4- (methyloxy) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

To a solution of ethyl 4- [4- (methyloxy) phenyl] -2,4-dioxobutanoate (600 mg, 2.397 mmol) in benzene (5 mL), 1- (1-methylethyl) -1H— Pyrazol-5-amine (300 mg, 2.397 mmol) was added and the reaction mixture was stirred at 62 ° C. overnight. The mixture was concentrated in vacuo and the residue was dissolved in acetic acid (3 mL). The solution was stirred at reflux for 1 hour and concentrated under vacuum. The residue was purified using column chromatography (silica gel, 0-100% EtOAc / hexanes) to give 530 mg (65%) of product. LCMS ES (M + H) = 340.1 ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.47-1.57 (m, 3H), 1.61-1.71 (m, 6H), 3 .88-3.96 (s, 3H), 4.55 (q, J = 7.2 Hz, 2H), 5.46 (m, 1H), 7.03-7.12 (m, 2H), 8 .13-8.25 (m, 3H), 8.36-8.43 (m, 1H).

Intermediate 62
1- (1-Methylethyl) -6- [4- (methyloxy) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 1- (1-methylethyl) -6- [4- (methyloxy) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (200 mg, 0.589 mmol), ethanol (4 mL) The title compound was prepared in the same manner as described for Intermediate 58 using and THF (1 mL), and sodium hydroxide (0.982 mL, 2.95 mmol). 181 mg (98%) of the final product was recovered. LCMS ES (M + H) = 312.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.51-1.63 (m, 6H), 3.85 (s, 3H), 5.35 (m, 1H), 7.11 (d, J = 9.1 Hz, 2H), 8.15 (s, 1H), 8.18-8.25 (m, 2H), 8.33 (s, 1H), 13.95 (br.s., 1H) ).

Example 113
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [4- (methyloxy) phenyl] -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

1- (1-methylethyl) -6- [4- (methyloxy) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (70 mg, 0.225 mmol), DMSO (3 mL), 3- (Aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (63.6 mg, 0.337 mmol) HCl salt, N-methylmorpholine (0.099 mL, 0.899 mmol), 1-hydroxy-7 The title compound was prepared in the same manner as described in Example 109 using azabenzotriazole (61.2 mg, 0.450 mmol), and EDC (86 mg, 0.450 mmol). The final product was recovered 89 mg (89%). LCMS ES (M + H) = 446.5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.54 (d, J = 6.8 Hz, 6H), 2.13 (s, 3H), 2.23 (s, 3H), 3.85 ( s, 3H), 4.41 (d, J = 4.8 Hz, 2H), 5.20-5.48 (m, 1H), 5.91 (s, 1H), 7.11 (d, J = 8.8 Hz, 2H), 8.11 (s, 1H), 8.24 (d, J = 8.8 Hz, 2H), 8.34 (s, 1H), 8.95 (m, 1H), 11 .58 (s, 1H).

Intermediate 63
Ethyl 2,4-dioxo-4- (4-pyridinyl) butanoate

Sodium metal (0.466 g, 20.26 mmol), 1- (4-pyridinyl) ethanone (1 g, 6.66 mmol), and diethylethanedioate (2.388 mL, 17.62 mmol) were used to give the title compound. , Prepared in the same manner as Intermediate 29. The crude product was purified using column chromatography (0-100% EtOAc / hexanes) to give 0.95 g of product (24%). LCMS ES (M + H) = 222.0. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.37-1.55 (m, 3H), 4.43 (q, J = 7.07 Hz, 2H), 7.06-7.16 (m, 1H), 7.72-7.92 (m, 2H), 8.82-8.94 (m, 2H).

Intermediate 64
Ethyl 1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

To a suspension of ethyl 2,4-dioxo-4- (4-pyridinyl) butanoate (442 mg, 1.997 mmol) in benzene (5 mL) was added 1- (1-methylethyl) -1H-pyrazol-5-amine. (250 mg, 1.997 mmol) was added and the reaction mixture was stirred at 62 ° C. overnight. The reaction mixture was concentrated in vacuo and the residue was purified using column chromatography (silica gel, 0-100% EtOAc / hexanes) to give 270 mg (43%) of product. LCMS ES (M + H) = 311.3 ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.54 (t, J = 7.2 Hz, 3H), 1.68 (d, J = 6.6 Hz, 6H), 4.58 (q, J = 7.1 Hz, 2H), 5.41-5.60 (m, 1H), 8.04-8.19 (m, 2H), 8.29 (s, 1H), 8.44-8.55 (m, 2H), 8.76-8.91 (m, 1H).

Intermediate 65
1- (1-Methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (100 mg, 0.322 mmol), ethanol (4 mL), THF (0 .8 mL), and sodium hydroxide (0.537 mL, 1.611 mmol) were used to prepare the title compound in the same manner as described for Intermediate 58. The final product was recovered 88 mg (97%). LCMS ES (M + H) = 283.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.58 (d, J = 6.4 Hz, 6H), 5.40 (m, 1H), 8.25 (d, J = 5.6 Hz, 2H) ), 8.32 (s, 1H), 8.44 (s, 1H), 8.79 (d, J = 5.6 Hz, 2H), 14.12 (br.s., 1H).

Example 114
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (60 mg, 0.213 mmol), DMSO (2 mL), 3- (amino Methyl) -4,6-dimethyl-2 (1H) -pyridinone (60.1 mg, 0.319 mmol) HCl salt, N-methylmorpholine (0.093 mL, 0.850 mmol), 1-hydroxy-7-azabenzotriazole The title compound was prepared in the same manner as described in Example 109 using (57.9 mg, 0.425 mmol), and EDC (81 mg, 0.425 mmol). The final product was recovered 66 mg (74%). LCMS ES (M + H) = 446.5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.56 (d, J = 6.0 Hz, 6H), 2.13 (br.s., 3H), 2.23 (br.s., 3H) ), 4.43 (m, 2H), 5.37 (m, 1H), 5.91 (br.s., 1H), 8.15-8.34 (m, 3H), 8.44 (s) , 1H), 8.78 (br.s., 2H), 9.00 (br.s., 1H), 11.58 (br.s., 1H).

Intermediate 66
Ethyl 4- (4-chlorophenyl) -2,4-dioxobutanoate

Sodium metal (0.143 g, 6.21 mmol) was dissolved in ethanol (3 mL) and the resulting solution was cooled in an ice bath. A mixture of 1- (4-chlorophenyl) ethanone (0.756 mL, 5.65 mmol) and diethylethanedioate (0.766 mL, 5.65 mmol) was added dropwise and the reaction mixture was stirred for 16 hours. The reaction mixture was quenched with ice water (5 mL) and acidified to ~ pH 3 with 1N HCl. The precipitate was collected by filtration and dried under high vacuum to give 1.39 g (97%) of product. LCMS ES (M + H) = 255.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.29 (m, 3H), 4.27 (d, J = 6.57 Hz, 2H), 7.60 (d, J = 7.58 Hz, 2H) ), 8.02 (d, J = 6.57 Hz, 2H).

Intermediate 67
Ethyl 6- (4-chlorophenyl) -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 4- (4-chlorophenyl) -2,4-dioxobutanoate (610 mg, 2.397 mmol), benzene (5 mL), 1- (1-methylethyl) -1H-pyrazol-5-amine (300 mg, The title compound was prepared in the same manner as described for Intermediate 61 using 2.397 mmol), and acetic acid (4 mL). The crude product was purified by column chromatography (silica gel, eluent: 0-100% EtOAc / hexane) to give 621 mg (75%) of product. LCMS ES (M + H) = 344.1. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.48-1.57 (m, 3H), 1.64-1.74 (m, 6H), 4.56 (q, J = 7.1 Hz, 2H), 5.46 (m, 1H), 7.49-7.55 (m, 2H), 8.15-8.18 (m, 2H), 8.21 (s, 1H), 8.42. (S, 1H).

Intermediate 68
6- (4-Chlorophenyl) -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 6- (4-chlorophenyl) -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (400 mg, 1.163 mmol), ethanol (6 mL), THF (1 mL ) Is used to prepare the title compound in the same manner as described for Intermediate 58, and sodium hydroxide (1.939 mL, 5.82 mmol) is added, where the reaction time is 2 hours. there were. The final product was recovered in 330 mg (90%). LCMS ES (M + H) = 315.8. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.56 (d, J = 6.8 Hz, 6H), 5.26-5.47 (m, 1H), 7.62 (d, J = 8 .6 Hz, 2H), 8.20 (s, 1H), 8.28 (d, J = 8.6 Hz, 2H), 8.38 (s, 1H), 14.03 (s, 1H).

Example 115
6- (4-Chlorophenyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

6- (4-Chlorophenyl) -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (70 mg, 0.222 mmol), DMSO (2 mL), 3- (amino Methyl) -4,6-dimethyl-2 (1H) -pyridinone HCl salt (62.7 mg, 0.333 mmol), N-methylmorpholine (0.097 mL, 0.887 mmol), 1-hydroxy-7-azabenzotriazole The title compound was prepared in the same manner as described in Example 109 using (60.3 mg, 0.443 mmol) and EDC (85 mg, 0.443 mmol). The final product was recovered 77 mg (78%). LCMS ES (M + H) = 450.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.55 (d, J = 6.6 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 4.41 ( d, J = 4.6 Hz, 2H), 5.34 (quin, J = 6.7 Hz, 1H), 5.91 (s, 1H), 7.64 (d, J = 8.6 Hz, 2H), 8.19 (s, 1H), 8.31 (d, J = 8.6 Hz, 2H), 8.39 (s, 1H), 8.97 (t, J = 4.7 Hz, 1H), 11. 58 (s, 1H).

Intermediate 69
Ethyl 2,4-dioxo-4- (2-thienyl) butanoate

Using sodium metal (0.180 g, 7.85 mmol), 1- (3-thienyl) ethanone (0.9 g, 7.13 mmol) and diethylethanedioate (0.967 mL, 7.13 mmol) to give the title compound Was prepared in the same manner as for intermediate 66. 1.41 g (87%) of product was recovered. LCMS ES (M + H) = 226.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.30 (m, 3H), 4.29 (q, J = 6.82 Hz, 2H), 6.96 (br.s., 1H), 7 .60-7.81 (m, 2H), 8.74 (br.s., 1H).

Intermediate 70
Ethyl 1- (1-methylethyl) -6- (3-thienyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 2,4-dioxo-4- (3-thienyl) butanoate (542 mg, 2.397 mmol), benzene (5 mL), 1- (1-methylethyl) -1H-pyrazol-5-amine (300 mg, 2.397 mmol) ), And acetic acid (5 mL), and the title compound was prepared in the same manner as described for Intermediate 61. The crude product was purified using column chromatography (silica gel, eluent: 0-100% EtOAc / hexanes) to give 590 mg (78%) of product. LCMS ES (M + H) = 315.8. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.53 (t, J = 6.8 Hz, 3H), 1.66 (d, J = 6.8 Hz, 6H), 4.56 (q, J = 7.1 Hz, 2H), 5.43 (spt, J = 6.7 Hz, 1H), 7.47 (dd, J = 5.1, 3.0 Hz, 1H), 7.84-7.95 (m , 1H), 8.08-8.18 (m, 2H), 8.32-8.43 (m, 1H).

Intermediate 71
1- (1-Methylethyl) -6- (3-thienyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 1- (1-methylethyl) -6- (3-thienyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (400 mg, 1.268 mmol), ethanol (5 mL), THF (1 mL ), And sodium hydroxide (2.114 mL, 6.34 mmol) were used to prepare the title compound in the same manner as described for Intermediate 58. 370 mg (100%) of the final product was recovered. LCMS ES (M + H) = 287.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.55 (d, J = 6.8 Hz, 6H), 5.34 (quin, J = 6.6 Hz, 1H), 7.72 (dd, J = 5.0, 3.0 Hz, 1H), 7.93 (dd, J = 5.0, 1.3 Hz, 1H), 8.15 (s, 1H), 8.34 (s, 1H), 8 .49 (dd, J = 3.0, 1.3 Hz, 1H), 13.97 (s, 1H).

Example 116
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (3-thienyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -6- (3-thienyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (70 mg, 0.244 mmol), DMSO (2 mL), 3- (amino Methyl) -4,6-dimethyl-2 (1H) -pyridinone (68.9 mg, 0.365 mmol) HCl salt, N-methylmorpholine (0.107 mL, 0.974 mmol), 1-hydroxy-7-azabenzotriazole The title compound was prepared in the same manner as described in Example 109 using (33.2 mg, 0.244 mmol) and EDC (93 mg, 0.487 mmol). The final product was recovered 75 mg (73%). LCMS ES (M + H) = 422.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.53 (d, J = 6.8 Hz, 6H), 2.13 (s, 3H), 2.23 (s, 3H), 4.41 ( d, J = 4.8 Hz, 2H), 5.30 (quin, J = 6.6 Hz, 1H), 5.91 (s, 1H), 7.71 (dd, J = 5.0, 3.0 Hz) , 1H), 7.92 (d, J = 5.0 Hz, 1H), 8.09 (s, 1H), 8.34 (s, 1H), 8.37 (d, J = 1.8 Hz, 1H) ), 8.79-8.95 (m, 1H), 11.58 (s, 1H).

Intermediate 72
Ethyl 3-methyl-1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 2,4-dioxo-4- (4-pyridinyl) butanoate (766 mg, 2.87 mmol), benzene (6 mL), and 3-methyl-1- (1-methylethyl) -1H-pyrazol-5-amine ( The title compound was prepared in the same manner as described for intermediate 64 using 400 mg, 2.87 mmol). The crude product was purified using column chromatography (silica gel, eluent: 0-30% MeOH / DCM) to give 95 mg (10%) of product. LCMS ES (M + H) = 325.3. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.48-1.56 (m, 3H), 1.61-1.73 (m, 6H), 2.77 (s, 3H), 4.56 (Q, J = 7.2 Hz, 2H), 5.37-5.50 (m, 1H), 8.02-8.16 (m, 3H), 8.76-8.83 (m, 2H) .

Intermediate 73
3-Methyl-1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 3-methyl-1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (36 mg, 0.111 mmol), ethanol (2 mL) The title compound was prepared in the same manner as described for Intermediate 58 using sodium hydroxide (0.185 mL, 0.555 mmol).
The final product was recovered 26 mg (79%). LCMS ES (M + H) = 297.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.54 (d, J = 6.4 Hz, 6H), 2.65 (s, 3H), 5.35 (m, 1H), 8.17 ( s, 1H) 8.24 (m, 2H), 8.78 (m, 2H).

Example 117
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -6- (4-pyridinyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

3-methyl-1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (20 mg, 0.067 mmol), DMSO (1 mL), 3- (Aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (19.10 mg, 0.101 mmol), N-methylmorpholine (0.030 mL, 0.270 mmol), 1-hydroxy-7-aza The title compound was prepared in the same manner as described in Example 109 using benzotriazole (18.37 mg, 0.135 mmol) and EDC (25.9 mg, 0.135 mmol). The final product was recovered 29 mg (100%). LCMS ES (M + H) = 431.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.52 (d, J = 6.57 Hz, 6H), 2.12 (s, 3H), 2.25 (s, 3H), 2.46 ( s, 3H), 4.40 (d, J = 5.0 Hz, 2H), 5.29 (quin, J = 6.7 Hz, 1H), 5.89 (s, 1H), 7.83 (s, 1H), 8.19 (d, J = 6.1 Hz, 2H), 8.64-8.89 (m, 3H), 11.55 (br.s., 1H).

Intermediate 74
Ethyl 1,6-bis (1,1-dimethylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 5,5-dimethyl-2,4-dioxohexanoic acid (392 mg, 1.958 mmol), benzene (10 mL), 1- (1,1-dimethylethyl) -3-methyl-1H-pyrazol-5-amine The title compound was prepared in the same manner as described for Intermediate 61 using (300 mg, 1.958 mmol), and acetic acid (2 mL). The crude product was purified by column chromatography (silica gel, eluent: 0-100% EtOAc / hexane) to give 530 mg (85%) of product. LCMS ES (M + H) = 318.3. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.43-1.52 (m, 12H), 1.84 (s, 9H), 2.67 (s, 3H), 4.50 (q, J = 7.07 Hz, 2H), 7.59 (s, 1H).

Intermediate 75
1,6-Bis (1,1-dimethylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

To a solution of ethyl 1,6-bis (1,1-dimethylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (528 mg, 1.663 mmol) in EtOH (8 mL), Sodium hydroxide (2.77 mL, 8.32 mmol) was added and the mixture was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure and the aqueous phase was acidified to ~ pH 3 using 1H HCl. The precipitate was filtered, washed with water and dried under high vacuum to give 445 mg (92%) of product. LCMS ES (M + H) = 289.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.49 (s, 9H), 1.76 (s, 9H), 2.51 (s, 3H), 7.51 (s, 1H).

Example 118
1,6-bis (1,1-dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide

1,6-bis (1,1-dimethylethyl) -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (70 mg, 0.242 mmol), DMSO (2 mL), 3- ( Aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (68.5 mg, 0.363 mmol), N-methylmorpholine (0.106 mL, 0.968 mmol), 1-hydroxy-7-azabenzotriazole ( The title compound was prepared in the same manner as described in Example 109 using 65.9 mg, 0.484 mmol) and EDC (93 mg, 0.484 mmol). The final product was recovered 91 mg (87%). LCMS ES (M + H) = 424.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.38 (s, 9H), 1.74 (s, 9H), 2.12 (s, 3H), 2.23 (s, 3H), 2.35 (s, 3H), 4.35 (d, J = 4.80 Hz, 2H), 5.88 (s, 1H), 7.15 (s) , 1H), 8.61 (t, J = 4.93 Hz, 1H), 11.52 (s, 1H).

Intermediate 76
Ethyl 4- [4- (methylthio) phenyl] -2,4-dioxobutanoate

Using sodium metal (0.160 g, 6.95 mmol), 1- [4- (methylthio) phenyl] ethanone (1.05 g, 6.32 mmol) and diethylethanedioate (0.856 mL, 6.32 mmol) The title compound was prepared in the same manner as for intermediate 66. 1.58 g (59%) of product was recovered. LCMS ES (M + H) = 266.9. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.29-1.50 (m, 3H), 2.41-2.62 (m, 3H), 4.23-4.49 (m, 2H) 7.15-7.38 (m, 2H), 7.89 (dd, J = 8.72, 2.15 Hz, 2H).

Intermediate 77
Ethyl 1- (1-methylethyl) -6- [4- (methylthio) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 4- [4- (methylthio) phenyl] -2,4-dioxobutanoate (851 mg, 3.20 mmol), benzene (6 mL), 1- (1-methylethyl) -1H-pyrazol-5-amine The title compound was prepared in the same manner as described for Intermediate 61 using (400 mg, 3.20 mmol), and acetic acid (3 mL). The crude product was purified by column chromatography (silica gel, eluent; 0-100% EtOAc / hexanes) to give 870 mg (63%) of product. LCMS ES (M + H) = 433.2. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.47-1.57 (m, 3H), 1.66 (d, J = 6.8 Hz, 6H), 2.58 (s, 3H), 4 .56 (q, J = 7.2 Hz, 2H), 5.38-5.55 (m, 1H), 7.36-7.46 (m, 2H), 8.12-8.19 (m, 2H), 8.22 (s, 1H), 8.40 (s, 1H).

Intermediate 78
Ethyl 1- (1-methylethyl) -6- [4- (methylsulfonyl) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Oxone (1712 mg, 2.79 mmol) was added to ethyl 1- (1-methylethyl) -6- [4- (methylthio) phenyl] -1H-pyrazolo [3,4-in acetone (6 mL) and water (2 mL). b] To a solution of pyridine-4-carboxylate (330 mg, 0.928 mmol) was added and the reaction mixture was stirred for 6 hours. The reaction mixture was quenched with water (10 mL) and then neutralized with aHCO ₃ solution. The mixture was extracted with EtOAc (3 ×) and the combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified using column chromatography (silica gel, 0-100% EtOAc / hexanes) to give 295 mg (82%) of product. LCMS ES (M + H) = 388.1. ¹ H
NMR (400 MHz, chloroform-d) δ ppm 1.54 (t, J = 7.2 Hz, 3H), 1.67-1.69 (d, J = 6.8 Hz, 6H), 3.14 (s, 3H), 4.58 (q, J = 7.2 Hz, 2H), 5.48 (spt, J = 6.7 Hz, 1H), 8.06-8.18 (m, 2H), 8.29 ( s, 1H), 8.39-8.44 (m, 2H), 8.47 (s, 1H).

Intermediate 79
1- (1-Methylethyl) -6- [4- (methylsulfonyl) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 1- (1-methylethyl) -6- [4- (methylsulfonyl) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (260 mg, 0.671 mmol), ethanol (4 mL) The title compound was prepared in the same manner as described for Intermediate 58 using, THF (1 mL) and sodium hydroxide (2N, 1.118 mL, 3.36 mmol). 231 mg (96%) of the final product was recovered. LCMS ES (M + H) = 360.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ
ppm 1.58 (d, J = 6.8 Hz, 6H), 3.30 (s, 3H), 5.34-5.49 (m, 1H), 8.11 (d, J = 8.6 Hz, 2H), 8.30 (s, 1H), 8.44 (s, 1H), 8.51 (d, J = 8.6 Hz, 2H).

Example 119
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [4- (methylsulfonyl) phenyl] -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide

1- (1-methylethyl) -6- [4- (methylsulfonyl) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (90 mg, 0.250 mmol), DMSO (2 mL), 3- (Aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (70.9 mg, 0.376 mmol), N-methylmorpholine (0.110 mL, 1.002 mmol), 1-hydroxy-7-aza The title compound was prepared in the same manner as described in Example 109 using benzotriazole (68.2 mg, 0.501 mmol) and EDC (96 mg, 0.501 mmol). The final product was recovered 106 mg (85%). LCMS ES (M + H) = 494.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.56 (d, J = 5.6 Hz, 6H), 2.13 (br.s., 3H), 2.23 (br.s., 3H) ), 4.42 (m, 2H), 5.36 (br.s., 1H), 5.91 (br.s., 1H), 8.11 (d, J = 7.3 Hz, 2H), 8.27 (br.s., 1H), 8.39-8.64 (m, 3H), 9.01 (br.s., 1H), 11.58 (br.s., 1H).

Intermediate 80
Ethyl 4- (4-bromophenyl) -2,4-dioxobutanoate

Using sodium metal (0.404 g, 17.58 mmol), 1- (4-bromophenyl) ethanone (3.5 g, 17.58 mmol), and diethylethanedioate (2.384 mL, 17.58 mmol), The title compound was prepared in the same manner as for Intermediate 66. 5.1 g (97%) of product was recovered. LCMS ES (M + H) = 299.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.22-1.37 (m, 3H), 4.25 (d, J = 6.57 Hz, 2H), 7.72 (m, 2H), 7.92 (m, 2H).

Intermediate 81
Ethyl 6- (4-bromophenyl) -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 4- (4-bromophenyl) -2,4-dioxobutanoate (956 mg, 3.20 mmol), benzene (10 mL), 1- (1-methylethyl) -1H-pyrazol-5-amine (400 mg The title compound was prepared in the same manner as described for Intermediate 61 using 3.20 mmol), and acetic acid (4 mL). The crude product was purified using column chromatography (silica gel, eluent: 0-100% EtOAc / hexane) to give 1.1 g (89%) of product. LCMS ES (M + H) = 388.1. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.49-1.57 (t, J = 67.2 Hz, 3H), 1.63-1.74 (d, J = 6.8 Hz6H), 4. 56 (q, J = 7.2 Hz, 2H), 5.46 (spt, J = 6.7 Hz, 1H), 7.65-7.71 (m, 2H), 8.04-8.15 (m , 2H), 8.21 (s, 1H), 8.42 (s, 1H).

Intermediate 82
1- (1-Methylethyl) -6- [4- (1H-pyrazol-4-yl) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

In a 5 mL microwave vial, add ethyl 6- (4-bromophenyl) -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (80 mg, 0.206 mmol), 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (56.0 mg, 0.288 mmol), 1,4-dioxane (2 mL) and sodium carbonate (0.206 mL, 0.412 mmol) was added and the mixture was degassed with nitrogen for 10 min. Next, PdP (Ph ₃ ) ₄ (19.05 mg, 0.016 mmol) was added and the vial was sealed. The reaction mixture was irradiated (microwave) at 120 ° C. overnight. The reaction mixture was filtered and concentrated under vacuum. The residue was purified using reverse phase HPLC to give 25 mg (35%) of product. LCMS ES (M + H) = 348.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.58 (d, J = 6.8 Hz, 6H), 5.38 (quin, J = 6.6 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 8.14-8.30 (m, 4H), 8.36 (s, 1H).

Example 120
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [4- (1H-pyrazol-4-yl) Phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

1- (1-methylethyl) -6- [4- (1H-pyrazol-4-yl) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (20 mg, 0.058 mmol), DMSO (1 mL), 3- (aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (16.29 mg, 0.086 mmol), N-methylmorpholine (0.025 mL, 0.230 mmol), 1- The title compound was prepared in the same manner as described in Example 109 using hydroxy-7-azabenzotriazole (15.67 mg, 0.115 mmol) and EDC (22.07 mg, 0.115 mmol). The final product was recovered 12 mg (43%). LCMS ES (M + H) = 482.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.56 (d, J = 6.4 Hz, 6H), 2.14 (s, 3H), 2.24 (s, 3H), 4.42 ( d, J = 4.8 Hz, 2H) 5.27-5.47 (m, 1H), 5.91 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 8.04 (Br.s., 1H), 8.15-8.21 (m, 1H), 8.27 (d, J = 8.3 Hz, 2H), 8.35-8.42 (m, 1H), 8.9 (t, J = 4.8 Hz, 1H), 11.58 (br.s., 3H).

Intermediate 83
Ethyl 1- (1,1-dimethylethyl) -3-methyl-6- [4- (methyloxy) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 4- [4- (methyloxy) phenyl] -2,4-dioxobutanoate (327 mg, 1.305 mmol), benzene (8 mL), 1- (1,1-dimethylethyl) -3-methyl- The title compound was prepared in the same manner as described for Intermediate 61 using 1H-pyrazol-5-amine (200 mg, 1.305 mmol), and acetic acid (2 mL). The crude product was purified using column chromatography (silica gel, eluent: 0-100% EtOAc / hexane) to give 0.41 g (85%) of product. LCMS ES (M + H) = 368.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.81 (s, 9H), 2.55 (s, 3H), 7.11 (d, J = 8.84 Hz, 2H), 7.89 ( s, 1H), 8.16 (d, J = 8.84 Hz, 2H).

Intermediate 84
1- (1,1-Dimethylethyl) -3-methyl-6- [4- (methyloxy) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 1- (1,1-dimethylethyl) -3-methyl-6- [4- (methyloxy) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (400 mg, 1.089 mmol The title compound was prepared in the same manner as described for Intermediate 75 using 3N sodium hydroxide (1.814 mL, 5.44 mmol), and EtOH (6 mL). 347 mg (94%) of product was recovered. LCMS ES (M + H) = 340.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.81 (s, 9H), 2.55 (s, 3H), 7.11 (d, J = 8.84 Hz, 2H), 7.89 ( s, 1H), 8.16 (d, J = 8.84 Hz, 2H).

Example 121
1- (1,1-Dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- [4- (methyloxy ) Phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide

1- (1,1-Dimethylethyl) -3-methyl-6- [4- (methyloxy) phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (1 mL) in DMSO (1 mL) 70 mg, 0.206 mmol) in a solution of 3- (aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (19.10 mg, 0.101 mmol), N-methylmorpholine (0.030 mL,. 270 mmol), 1-hydroxy-7-azabenzotriazole (18.37 mg, 0.135 mmol) and EDC (25.9 mg, 0.135 mmol) were added and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (10 mL), stirred for 10 minutes and filtered. The contents were dried under high vacuum and 71 mg (71%) was recovered. LCMS ES (M + H) = 474.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.79 (s, 9H), 2.12 (s, 3H), 2.25 (s, 3H), 2.39 (s, 3H), 3 .33 (s, 1H), 4.38 (d, J = 4.80 Hz, 2H), 5.88 (s, 1H), 7.10 (d, J = 8.84 Hz, 2H), 7.61 (S, 1H), 8.16 (d, J = 8.84 Hz, 2H), 8.70 (s, 1H), 11.53 (s, 1H).

Intermediate 85
Ethyl 1- (1,1-dimethylethyl) -3-methyl-6-{[(trifluoromethyl) sulfonyl] oxy} -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Trifluoromethanesulfonic anhydride (0.457 mL, 2.70 mmol) was added to ethyl 1- (1,1-dimethylethyl) -3-methyl-6-oxo-6,7-dihydro-1H in pyridine (10 mL). -A solution of pyrazolo [3,4-b] pyridine-4-carboxylate (500 mg, 1.803 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The contents were diluted with EtOAc and washed with saturated NaHCO ₃ and then with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography (0-100% DCM: Hex) to give the final product as a solid 670 mg (91%). LCMS ES (M + H) = 410.0. ¹ H
NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.38 (t, J = 7.07 Hz, 3H), 1.71 (s, 9H), 2.58 (s, 3H), 4.46 (q, J = 7.07 Hz, 2H), 7.63 (s, 1H).

Intermediate 86
Ethyl 1- (1,1-dimethylethyl) -3-methyl-6- (3-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 1- (1,1-dimethylethyl) -3-methyl-6-{[(trifluoromethyl) sulfonyl] oxy} -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (100 mg, 0 .244 mmol) 3-pyridinylboronic acid (39.0 mg, 0.318 mmol), saturated aqueous NaHCO ₃ (1 mL) and 1,4-dioxane (3 mL) were degassed with nitrogen (10 min) followed by PdCl ₂ (Dppf) -CH ₂ Cl ₂ adduct (9.97 mg, 0.012 mmol) was added. The sealed mixture was irradiated (microwave) at 120 ° C. for 40 minutes. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (0-100% EtOAc / hexanes). The final product was recovered as a solid 72 mg (87%). LCMS ES (M + H) = 339.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ
ppm 1.46-1.57 (m, 3H), 1.90 (s, 9H), 2.72 (s, 3H), 4.45-4.64 (m, 2H), 7.47 (dd , J = 8.08, 4.80 Hz, 1H), 8.03 (s, 1H), 8.46 (dt, J = 8.08, 2.02 Hz, 1H), 8.72 (dd, J = 4.80, 1.52 Hz, 1H), 9.43 (d, J = 1.52 Hz, 1H).

Intermediate 87
1- (1,1-Dimethylethyl) -3-methyl-6- (3-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 1- (1,1-dimethylethyl) -3-methyl-6- (3-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate (68 mg, 0.201 mmol) was added to ethanol. Suspended in (2 mL) followed by addition of sodium hydroxide (0.335 mL, 1.005 mmol). The mixture was stirred at room temperature for 2.5 hours. The mixture was concentrated and the residue was diluted with water (1 mL) and acidified to pH 3 using 1N HCl. The precipitate was collected by filtration and further dried under high vacuum to give the product as the HCl salt 60 mg (86%). LCMS ES (M + H) = 311.5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.82 (s, 9H), 2.60 (s, 3H), 7.60 (dd, J = 7.96, 4.67 Hz, 1H), 8.08 (s, 1H), 8.57 (dt, J = 8.34, 1.89 Hz, 1H), 8.70 (dd, J = 4.80, 1.52 Hz, 1H), 9.39 (D, J = 1.52 Hz, 1H), 14.03 (br.s., 1H).

Example 122
1- (1,1-Dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- (3-pyridinyl)- 1H-pyrazolo [3,4-b] pyridine-4-carboxamide.

1- (1,1-dimethylethyl) -3-methyl-6- [3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (58 mg, 0.167 mmol), 3- ( (Aminomethyl) -4,6-dimethyl-2 (1H) -pyridinone (47 mg, 0.251 mmol), N-methylmorpholine (0.092 mL, 0.836 mmol), 1-hydroxy-7-azabenzotriazole (46 mg, The title compound was prepared in the same manner as described in Example 121 using 0.334 mmol), EDC (64 mg, 0.334 mmol), and DMSO (1 mL). 73 mg (96%) of product was recovered. LCMS ES (M + H) = 445.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.81 (s, 9H), 2.12 (s, 3H), 2.25 (s, 3H), 2.42 (s, 3H), 4 .39 (d, J = 5.05 Hz, 2H), 5.89 (s, 1H), 7.59 (dd, J = 8.08, 4.80 Hz, 1H), 7.78 (s, 1H) 8.55 (dt, J = 8.15, 1.86 Hz, 1H), 8.68 (dd, J = 4.80, 1.52 Hz, 1H), 8.74 (t, J = 0.05 Hz) , 1H) 9.38 (d, J = 1.77 Hz, 1H), 11.54 (s, 1H).

Example 123
3-Bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3 4-b] pyridine-4-carboxamide

3-Bromo-1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (93 mg, 0.258 mmol), 3- (aminomethyl) -4 6-Dimethyl-2 (1H) -pyridinone hydrochloride (64 mg, 0.336 mmol), HOBT (60 mg, 0.387 mmol) and EDC (74 mg, 0.387 mmol) were suspended in DMSO (14 mL) and 10% at room temperature. Stir for minutes and then add DIEA (0.9 mL, 5.16 mmol). After stirring for 2 hours, 4-methylmorpholine (1 mL, 9.04 mmol) was added. The reaction mixture was first stirred at room temperature for 21 hours and then at 80 ° C. (aluminum heating block) for 31 hours. The reaction mixture was cooled to room temperature and then a cold, weakly basic solution (pH˜8-10) of water (100 mL) and 1N Na ₂ CO ₃ (8 mL) was added dropwise. After stirring for 20 minutes, the contents were extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to a residue. Dissolve crude residue in 10% MeOH / DCM, silica gel chromatography (eluent: 10% to 95% gradient of EtOAc / hexanes, then _{10% (5% NH 4 OH} / MeOH) / DCM and EtOAc, 10 to 90% gradient) Purified by The product was recovered as an off-white solid (35 mg, 27%). LCMS ES (M + H) = 494.1 / 496.0. ¹ H NMR (400 MHz, chloroform-d) δ 11.58 (br.s., 1H), 8.11 (dd, J = 1.89, 7.71 Hz, 2H), 7.68 (br.s., 1H), 7.60 (br.s., 1H), 7.44-7.53 (m, 3H), 5.92 (s, 1H), 5.42 (quin, J = 6.69 Hz, 1H ), 4.63 (br.s., 1H), 2.41 (br.s., 3H), 2.11 (br.s., 3H), 1.62 (d, J = 6.57 Hz, 6H).

Intermediate 88
3-Bromo-1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 3-bromo-1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (112 mg, 0.288 mmol), THF (0.5 mL) and Suspended in ethanol (1.5 mL), followed by addition of 3N NaOH (150 μL, 0.433 mmol). The reaction mixture was stirred at 55 ° C. for 3 hours and then cooled to room temperature. The reaction mixture was diluted with water (1.5 mL), cooled in an ice bath and acidified by dropwise addition of 1N HCl. The mixture was extracted with EtOAc. The organic layer was separated and concentrated under vacuum to give a solid that was dried under high vacuum for 3 hours. The product was obtained as a pale yellow solid (93.6 mg, 90%). LCMS ES (M + H) = 360.0 / 362.2. ¹ H NMR (400 MHz, MeOD) δ · 8.22 (dd, J = 1.52, 8.08 Hz, 2H), 8.05 (s, 1H), 7.48-7.59 (m, 3H) , 5.47 (quin, J = 6.76 Hz, 1H), 1.63 (d, J = 6.82 Hz, 6H)

Intermediate 89
Ethyl 3-bromo-1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (120 mg, 0.388 mmol) is suspended in acetic acid (2 mL) followed by bromine. (26 μL, 0.504 mmol) was added. The reaction mixture was stirred with heating at 80 ° C. After 1 hour, bromine (26 μL, 0.504 mmol) was added again and the reaction mixture was heated at 80 ° C. for an additional 2 hours. After cooling to room temperature, the solution was added to a saturated aqueous solution of sodium bicarbonate (6 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic layers were concentrated under vacuum. The crude product was purified by silica gel chromatography (eluent: EtOAc / hexane, 0-50% gradient). The product was recovered as a white powder (112 mg, 74%). LCMS ES (M + H) = 388.0 / 390.2. ¹ H NMR (400 MHz, chloroform-d) δ 8.18 (dd, J = 1.52, 8.08 Hz, 2H), 8.00 (s, 1H), 7.48-7.58 (m, 3H) , 5.47 (quin, J = 6.76 Hz, 1H), 4.58 (q, J = 7.16 Hz, 2H), 1.65 (d, J = 6.82 Hz, 6H), 1.52 ( t, J = 7.20 Hz, 3H).

Intermediate 90
Ethyl 1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 2,4-dioxo-4-phenylbutanoate (5 g, 22.7 mmol), 1- (1-methylethyl) -1H-pyrazol-5-amine (2.84 g, 22.7 mmol), benzene (70 mL ), And acetic acid (44 mL) were used to prepare the title compound in the same manner as described for Intermediate 61. The crude product was purified by silica gel chromatography (eluent: 0-100% EtOAc / hexanes) to give 6.72 g (95%) as an off-white solid. LCMS ES (M + H) = 310.5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 8.17-8.28 (m, 3H), 7.49-7.64 (m, 3H), 5.38 ( quin, J = 6.69 Hz, 1H), 4.49 (q, J = 7.07 Hz, 2H), 1.57 (d, J = 6.57 Hz, 6H), 1.44 (t, 3H).

Example 124
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-nitrophenyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide

1- (1-Methylethyl) -3-nitro-6-phenyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (24 mg, 0.074 mmol), 3- (aminomethyl) -4 6-Dimethyl-2 (1H) -pyridinone hydrochloride (18 mg, 0.096 mmol), HOAT (17 mg, 0.110 mmol) and EDC (21 mg, 0.110 mmol) were suspended in DMSO (800 μL) and the reaction mixture was Stir at room temperature. Then 4-methylmorpholine (41 μL, 0.368 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was added dropwise with a cold, weakly basic solution (pH˜8-10) of water (3 mL) and 1N Na ₂ CO ₃ (0.5 mL). After stirring for 20 minutes, the precipitated solid was collected by vacuum filtration and washed with water. The solid was dried under high vacuum (72 hours). The product was collected as an off-white powder (28 mg, 82%). LCMS ES (M + H) = 461.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (br.s., 1H), 8.42 (s, 1H), 8.02 (ddd, J = 1.14, 4.99, 7. 77 Hz, 2H), 7.99 (s, 1H), 7.86 (td, J = 1.26, 7.58 Hz, 1H), 7.72-7.77 (m, 1H), 5.90 ( s, 1H), 5.04 (quin, J = 6.69 Hz, 1H), 4.41 (d, J = 4.55 Hz, 1H), 3.34 (s, 2H), 2.22 (s, 3H), 2.12 (s, 3H), 1.49 (d, J = 6.57 Hz, 6H).

Intermediate 91
1- (1-Methylethyl) -6- (2-nitrophenyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid

Ethyl 1- (1-methylethyl) -3-nitro-6-phenyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate is suspended in THF (0.5 mL) and ethanol (1 mL). This was followed by the addition of 3N aqueous NaOH (50 μL). The reaction mixture was heated at 55 ° C. for 1 hour and then cooled to room temperature. Volatiles were removed under vacuum and the residue was dissolved in water (1.5 mL). The reaction mixture was cooled in an ice bath and acidified by the dropwise addition of 1N HCl. After stirring for 20 minutes, the precipitated solid was collected by vacuum filtration and dried under high vacuum for 16 hours overnight. The product was recovered as a white solid (24.5 mg, 76%). LCMS ES (M + H) = 327.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.14 (br.s., 1H), 8.43 (s, 1H), 8.04 (dd, J = 1.14, 7.96 Hz, 1H) 7.98-8.02 (m, J = 1.26 Hz, 2H), 7.86 (td, J = 1.26, 7.58 Hz, 1H), 7.72-7.80 (m, 1H) ), 5.09 (qd, J = 6.57, 6.74 Hz, 1H), 1.51 (d, J = 6.57 Hz, 6H).

Intermediate 92
Ethyl 1- (1-methylethyl) -6- (2-nitrophenyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxylate

Ethyl 1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylate (120 mg, 0.388 mmol) was dissolved in concentrated nitric acid (1.7 mL) followed by Concentrated sulfuric acid (0.200 mL) was added and the reaction mixture was stirred at room temperature. After 40 minutes, the reaction mixture was cooled in an ice bath, diluted with water (3 mL) with stirring, and then slowly diluted with saturated Na ₂ CO ₃ (1 mL). The reaction mixture was extracted with EtOAc (2 × 6 mL). The combined organic layers were concentrated under vacuum and the crude product was purified by silica gel chromatography (eluent: EtOAc / hexane, 0-70% gradient). The product was recovered as a white solid (35 mg, 26%). LCMS ES (M + H) = 355.2. ¹ H NMR (400 MHz, chloroform-d) δ 8.46 (s, 1H), 7.99 (s, 1H), 7.94 (dd, J = 1.14, 7.96 Hz, 1H), 7.76 −7.81 (m, 1H), 7.73 (td, J = 1.26, 7.58 Hz, 1H), 7.59-7.66 (m, 1H), 5.25 (ddd, J = 6.57, 6.69, 13.52 Hz, 1H), 4.51-4.59 (m, 2H), 1.61 (d, J = 6.82 Hz, 6H), 1.52 (t, J = 7.07 Hz, 3H).

Example 125
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-propyl-1H-pyrazolo [3,4-b] Pyridine-4-carboxamide

1- (1-Methylethyl) -6-propyl-1H-pyrazolo [3,4-b] pyridine-4-carboxylic acid (70 mg, 0.283 mmol), DMSO (3 mL), 3- (aminomethyl) -4 , 6-Dimethyl-2 (1H) -pyridinone (80 mg, 0.425 mmol), N-methylmorpholine (0.124 mL, 1.132 mmol), 1-hydroxy-7-azabenzotriazole (77 mg, 0.566 mmol), The title compound was prepared in the same manner as described in Example 109 using and EDC (109 mg, 0.566 mmol). The collected solid was washed with water and methanol and dried under high vacuum to give 73 mg (68%) of product. LCMS ES (M + H) = 382.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82-1.10 (m, 3H), 1.48 (d, J = 6.8 Hz, 6H ), 1.77 (m, 2H), 2.13 (s, 3H), 2.21 (s, 3H), 2.85 (t, J = 7.6 Hz, 2H), 4.36 (d, J = 4.8 Hz, 2H), 5.20 (m, 1H), 5.90 (s, 1H), 7.38-7.58 (m, 1H), 8.26 (s, 1H), 8 .73 (t, J = 4.7 Hz, 1H), 11.57 (br.s., 1H).

Intermediate 93
3- (Aminomethyl) -6-ethyl-4-methyl-2 (1H) -pyridinone

Process 1
2,4-hexane dione (2.283 g, 20 mmol) and cyanoacetamide (1.682 g, 20.00 mmol) were added to ethanol (20 mL). The contents were initially heterogeneous but gradually melted as it approached about 70 ° C. Next, piperidine (1.976 mL, 20.00 mmol) was added and stirred while warming to reflux. After 30 minutes, the heterogeneous contents were removed from the heat and stirred while cooling to room temperature. The contents were filtered under vacuum to give a pale yellowish solid and a yellow filtrate. The collected solid filter cake was washed with a large amount of water to remove the yellow color. The final product was recovered as a fine white crystalline solid (1.66 g after drying). LCMS ES (M + H) = 163.2. ¹ H NMR (400 MHz, chloroform-d) δ · ppm 1.34 (t, J = 7.58 Hz, 3H) 2.47 (s, 3H) 2.71 (q, J = 7.58 Hz, 2H), 6 .12 (s, 1H).

Process 2
To a stirred solution of 6-ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.462 g, 9.01 mmol) in methanol (50 mL) cooled to 0 ° C. Di-tert butoxycarbonyl anhydride (4.19 mL, 18.03 mmol) and nickel (II) chloride hexahydrate (0.214 g, 0.901 mmol) were added. Sodium borohydride (2.387 g, 63.1 mmol) was added in portions over 30 minutes, then the mixture was warmed to room temperature and stirred overnight. Additional sodium borohydride (2.387 g, 63.1 mmol) was added and the reaction was again stirred overnight. Diethylenetriamine (0.979 mL, 9.01 mmol) was added and the reaction mixture was stirred for 30 minutes at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate (20 mL) and extracted with sodium bicarbonate (2 × 10 mL). The organics were dried with sodium sulfate and concentrated. The residue was dissolved in chloroform (25 mL) and TFA (3.47 mL, 45.1 mmol) was added. The reaction was heated to 50 ° C. for 3 hours, then cooled to room temperature and concentrated. The reaction mixture was concentrated in vacuo and the crude product was purified by reverse phase HPLC (eluent; 0-30% gradient ACN in H 2 O, 0.1% TFA) to give the title compound (TFA salt, 1.37 g). Yield 54.1%) as a white solid. LC-MS (ES) m / z = 167 [M + H] +. ¹ H NMR (400 MHz, DMSO-d) δ ppm 1.12 (t, J = 7.58 Hz, 3H), 2.20 (s, 3H), 2.44 (q, J = 7.58 Hz, 2H) 3.78-3.83 (m, 2H), 6.01 (s, 1H), 7.75-7.9 (brs, 3H), 11.86 (s, 1H).

Intermediate 94
3- (Aminomethyl) -5-fluoro-4,6-dimethyl-2 (1H) -pyridinone

Process 1
2,4-Pentanedione (12 g, 120 mmol) was suspended in deuterated MeCN (39 mL), to which Selectfluor (44.7 g, 120 mmol) was added in one portion. The resulting paste was then heated to 50 ° C. in an oil bath. After 5 minutes, an exotherm was observed and the mixture was removed from the oil bath. The mixture was then heated at 50 ° C. for 1 hour. The mixture was then aged for 16 hours at room temperature and then distilled under vacuum. The desired product was distilled at 40-15C at 10-15 torr and recovered as a pale yellowish liquid (1.8 mL, 1.95 g). The lower purity fraction (approximately 80%) was distilled at 25-20 ° C. and 15-20 torr and collected as a pale yellowish liquid (3.33 g). ¹ H NMR (400 MHz, acetonitrile-d ₃ ) δ ppm 2.24 (s, 3 H), 2.26 (s, 3 H), 5.46 (d, J = 48.0 Hz, 1 H).

Process 2
Of 3-fluoro-2,4-pentanedione (247 mg, 2.10 mmol), cyanoacetamide (176 mg, 2.1 mmol, 1 eq) and piperidine (0.21 mL, 2.1 mmol, 1 eq) in 3 mL EtOH. The mixture was heated at 85 ° C. for 16 hours, resulting in a clear but dark brown solution. The mixture was concentrated under vacuum. The residue was taken up in 2 mL of 1N HCl to give a suspension that was filtered. The collected tan solid was dried under vacuum to give 80 mg of the desired product. ¹ H NMR (400 MHz, chloroform-d) δ ppm 2.33 (s, 3H), 2.42 (s, 3H).

Process 3
5-Fluoro-4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.0 g, 6.02 mmol) suspended in 50 mL of HOAc at room temperature and a dark brownish solution Got. NaOAc (1.0 g, 12.3 mmol, 2 eq), PtO ₂ (20 mg) and 5% Pd / C (1.3 g) were packed into a 500 mL Parr bottle followed by some acetic acid under nitrogen. Moistened with. The substrate solution was then added and rinsed with another 50 mL of acetic acid. The mixture was hydrogenated under 40 psi pressure. The initial drop in hydrogen pressure refilled the vessel. The mixture was hydrogenated for 6 hours. The mixture was filtered through celite and concentrated in vacuo to give a solid residue that was suspended in 6 mL of concentrated HCl to give a paste. The paste was filtered and the cake was washed with 1 mL concentrated HCl (repeat). The filtrate was concentrated under vacuum. The solid residue was dissolved as a suspension in 0.4 mL concentrated HCl and 6 mL EtOH and stored in the freezer for 2 hours followed by filtration. The cake was washed with 2 mL of cold EtOH (repeat). The solid was dried under vacuum at room temperature for 18 hours to give the title compound as a cream solid (1.03 g). LC-MS (ES) m / z = 171 [M + H] +, and main peak, 154. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm, 2.20 (d, J = 3.0 Hz, 3H), 2.22 (d, J = 2.0 Hz, 3H), 3.83 (q, J = 5.2 Hz, 2H), 7.99 (br.s., 3H), 11.99 (br.s., 1H).

Assay protocol

Part A Compound Preparation A 10 mM stock of compound is prepared from solids in 100% DMSO.
2. Seed compound in rows 1 and 13 in a 384 well grainer plate (Cat # 781280).
3. Set up a 11-step serial dilution (1: 3 dilution, rows 6 and 18 are DMSO controls) on the multi-probe device.
4). Dispense 100 nL of compound from the dilution plate to the reaction plate (Corning, 384-well, Cat # 3706) using a Hummingbird.

Part B Reagent Preparation Prepare the following solutions:
1. Prepare 2 × assay buffer mix of 50 mM Tris pH 8, 5 mM MgCl ₂ , 4 mM DTT, 0.00185% Tween-20, and 7 μg / mL Hela nucleosome (GRITs36431) at final concentration.
2. Prepare 2 × EZH2 (GRITS37108) enzyme mix with a final enzyme concentration of 10 nM in assay buffer.
3. Prepare a 2 × mix of 0.24 μM unlabeled SAM (Sigma) and 0.02 μCi / μL ³ H-SAM (Perkin Elmer) labeled and unlabeled SAM in ddH 2 O at final concentrations.
Prepare a 500 μM SAH quench solution in ddH ₂ O with the addition of 4.5-10 drops of concentrated HCl.
5. Prepare 6 mg / mL RNA-bound SPA beads (Perkin Elmer) suspended in 0.2 M citric acid (pH 2.2).

Part C Assay Reaction in 384-well Corning Plate In a reaction plate that has been dispensed with 100 nL of compound, 1.5 μL of the enzyme-free control (assay buffer mix) is dispensed into column 18 of the plate.
Dispense 2.5 μL of enzyme mix into the remaining wells of the plate. Centrifuge plates to mix and incubate for 30 minutes at room temperature.
Dispense 3.5 μL of substrate mix into all wells to initiate the reaction. The plate is centrifuged for mixing and incubated for 2 hours at room temperature.
4. Stop the reaction with 10 μL of 500 μM SAH solution (final concentration 250 μM).
5. Dispense 10 μL of 6 mg / mL RNA-bound SPA beads prepared in 0.2 M citric acid (pH 2.2) using an evolution device. While adding to the plate, the beads are constantly agitated to prevent the beads from precipitating.
6). Seal the plate with a Perkin Elmer top seal and allow the beads to equilibrate in the plate for at least 30 minutes at room temperature.
7). Centrifuge the plate at> 2000 rpm (657 rcf) for 1 minute. After at least 5 hours of incubation, the plate is read in Microbeta. The plate is read immediately and the signal increases over time.
Reagent addition can be done manually or using an automated liquid handling device.
* The final DMSO concentration in this assay is 1%.
* Positive control is in column 6; negative control is in column 18.
* The final starting concentration of the compound is 100 μM.

Part D Data Analysis Results were analyzed using a two-parameter IC ₅₀ from the GraFit data analysis program (Erithacus Software Ltd, PO Bos 274, Horley, Surrey UK; www.erithacus.com).

The compounds of several of the above examples gave the following IC ₅₀ data: Example 1, 475; Example 2, 806; Example 4, 116; Example 5, 705; Example 6, 695; Examples 7, 1296; Examples 8, 167; Examples 9, 1309; Examples 10, 569; Examples 11, 18; Examples 12, 55; Examples 13, 55; Examples 14, 735; 179; Examples 16, 105; Examples 17, 2591; Examples 18, 40; Examples 19, 3372; Examples 20, 4647; Examples 21, 1040; Examples 22, 1362; Examples 25, 685; Examples 26, 673; Examples 27, 24; Examples 28, 348; Examples 29, 234; Examples 30, 154; Examples 31, 232; Examples 32 and 8 Examples 35 and 673; Examples 36 and 924; Examples 37 and 1095; Examples 38 and 392; Examples 41 and 86; Examples 42 and 56; Examples 43 and 204; Examples 44 and 74; Examples 45 and 248; Examples 46 and 128; Examples 47 and 88; Examples 48 and 198; Examples 49 and 115; Examples 50 and 81; Examples 51 and 161; 53, 436; Examples 54, 514; Examples 55, 260; Examples 56, 2111; Examples 57, 784; Examples 58, 78; Examples 59, 155; Examples 60, 198; 112; Examples 62 and 581; Examples 63 and 96; Examples 64 and 79; Examples 65 and 55; Examples 66 and 81; Examples 67 and 58; Examples 68 and 76; Examples 70 and 1893; Examples 71 and 402; Examples 72 and 171; Examples 73 and 533; Examples 74 and 151; Examples 75 and 131; Examples 76 and 82; Examples 77 and 52; Examples 78 and 43; 140; Examples 80 and 71; Examples 81 and 30; Examples 82 and 108; Examples 83 and 43; Examples 84 and 99; Examples 85 and 31; Examples 86 and 142; Examples 88 and 52; Examples 89 and 67; Examples 90 and 173; Examples 92 and 76; Examples 93 and 83; Examples 94 and 103; Examples 95 and 489; Examples 97, 55; Examples 99, 25044; Examples 100, 5747; Examples 103, 373; Examples 105, 315; Examples 106, 119; Examples 107, 75; Examples 109, 207; 231; Examples 111 and 367; Examples 112 and 693; Examples 113 and 248; Examples 114 and 199; Examples 117 and 190; Examples 118 and 273; Examples 119 and 333; 121,407; Examples 122,153; Examples 123,218; Examples 124,1052; Examples 125,2164.

  The values in this table are at a single-point-in-time, and repeated assays showed slightly different values for any test runs and compounds.

  The compounds of the invention are used as described above and are not considered to have unacceptable adverse effects if used in accordance with normal scientific medical practice.

  The foregoing examples are provided to illustrate and explain the present invention and are not intended to limit the invention in any way. What is reserved to the inventor can be found by referring to the claims.

Claims (6)

A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating cancer in a cancer patient :

{Where
X and Z are hydrogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl , ( C ₃ -C ₈ ) cycloalkyl , ( C ₃ -C ₈ ) Cycloalkyl- (C ₁ -C ₈ ) alkyl or-(C ₂ -C ₈ ) alkenyl , ( C ₅ -C ₈ ) cycloalkenyl , ( C ₅ -C ₈ ) cycloalkenyl- (C ₁ -C ₈ ) alkyl or - _(C 2 -C _{8) alkenyl,} (C 6 _{-C 10)} bicycloalkyl, hetero cycloalkyl, hetero cycloalkyl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈₎ alkenyl , the aryl, the aryl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈₎ alkenyl, f heteroaryl, f heteroaryl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈ ) Alkenyl, halo, cyano, -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -CONR ^a NR ^a R ^b , -SR ^a , -SOR ^a , -SO ₂ R ^a , -SO ₂ NR ^a R ^b , nitro, —NR ^a R ^b , —NR ^a C (O) R ^b , —NR ^a C (O) NR ^a R ^b , —NR ^a C (O) OR ^a , —NR ^a SO ₂ R ^b , -NR ^a SO ₂ NR ^a R ^b , -NR ^a NR ^a R ^b , -NR ^a NR ^a C (O) R ^b , -NR ^a NR ^a C (O) NR ^a R ^b , -NR ^a NR ^a Independently selected from the group consisting of C (O) OR ^a , —OR ^a , —OC (O) R ^a , and —OC (O) NR ^a R ^b ;
Y is H or halo;
R ¹ is (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl , ( C ₃ -C ₈ ) cycloalkyl , ( C ₃ -C ₈ ) cycloalkyl -(C ₁ -C ₈ ) alkyl or-(C ₂ -C ₈ ) alkenyl , ( C ₅ -C ₈ ) cycloalkenyl , ( C ₅ -C ₈ ) cycloalkenyl- (C ₁ -C ₈ ) alkyl or- _(C 2 -C ₈₎ alkenyl, _(C 6 _{-C 10)} bicycloalkyl, hetero cycloalkyl, hetero cycloalkyl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈₎ alkenyl, the aryl , the aryl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈₎ alkenyl, f heteroaryl, f heteroaryl - _(C 1 -C ₈₎ alkyl or - _(C 2 -C ₈₎ alkenyl ^{_{, -COR a, -CO 2 R a}} , -CONR a R b, be a -CONR ^a NR ^a R ^b;
R ³ is hydrogen, (C ₁ -C ₈ ) alkyl, cyano, trifluoromethyl, —NR ^a R ^b , or halo;
R ⁶ is hydrogen, halo, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl , ( C ₃ -C ₈ ) cycloalkyl , ( C ₃ -C ₈₎ cycloalkyl - _(C 1 -C ₈₎ alkyl, _(C 5 -C ₈₎ cycloalkenyl, _(C 5 -C ₈₎ cycloalkenyl - _(C 1 -C _{8) alkyl,} (C 6 _{-C 10)} bicycloalkyl, hetero cycloalkyl, hetero cycloalkyl - _(C 1 -C ₈₎ alkyl, the aryl, the aryl - _(C 1 -C ₈₎ alkyl, f heteroaryl, f heteroaryl _- (C 1 _-C 8) Alkyl, cyano, -COR ^a , -CO ₂ R ^a , -CONR ^a R ^b , -CONR ^a NR ^a R ^b , -SR ^a , -SOR ^a , -SO ₂ R ^a , -SO ₂ NR ^a R ^b , Nitro ^{-NR a R b, -NR a C} (O) R b, -NR a C (O) NR a R b, -NR a C (O) OR a, -NR a SO 2 R b, -NR a SO ₂ NR ^a R ^b , —NR ^a NR ^a R ^b , —NR ^a NR ^a C (O) R ^b , —NR ^a NR ^a C (O) NR ^a R ^b , —NR ^a NR ^a C (O) OR ^a , —OR ^a , —OC (O) R ^a , and —OC (O) NR ^a R ^b are selected;
Where (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are , Halo, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₅ -C ₈ ) cycloalkenyl, (C ₁ -C ₆ ) haloalkyl, cyano, —COR ^a , —CO ₂ R ^a , —CONR ^a R ^b , —SR ^a , —SOR ^a , —SO ₂ R ^a , —SO ₂ NR ^a R ^b , nitro, —NR ^a R ^b , —NR ^a C (O) R ^b , — NR ^a C (O) NR ^a R ^b , —NR ^a C (O) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —OR ^a , —OC (O) R ^a , -OC (O) NR 1, 2 or 3 independently selected from the group consisting of ^a R ^b , heterocycloalkyl, aryl, heteroaryl, aryl (C ₁ -C ₄ ) alkyl, and heteroaryl (C ₁ -C ₄ ) alkyl Optionally substituted by a group;
Wherein the aryl, heteroaryl, aryl (C ₁ -C ₄ ) alkyl, or heteroaryl (C ₁ -C ₄ ) alkyl aryl or heteroaryl moiety is halo, (C ₁ -C ₆ ) alkyl, ( C ₃ -C _{8) cycloalkyl, (C} 5 -C _{8) cycloalkenyl, (C} 1 -C ₆₎ haloalkyl, ^{_{cyano, -COR a, -CO 2 R a}} , -CONR a R b, -SR a, -SOR ^a , -SO ₂ R ^a , -SO ₂ NR ^a R ^b , nitro, -NR ^a R ^b , -NR ^a C (O) R ^b , -NR ^a C (O) NR ^a R ^b , -NR ^a C (O) OR ^a , —NR ^a SO ₂ R ^b , —NR ^a SO ₂ NR ^a R ^b , —OR ^a , —OC (O) R ^a , and —OC (O) NR ^a R ^b Selected independently of group It may be substituted by 2 or 3 groups; and,
R ^a and R ^b are each independently hydrogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl. , (C ₅ -C ₈ ) cycloalkenyl, (C ₆ -C ₁₀ ) bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein (C ₁ -C ₈ ) alkyl, (C _2- C _{8) alkenyl, (C} 2 -C ₈₎ alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl or heteroaryl group, halo, _{hydroxy, (C} 1 -C ₄₎ alkoxy, amino, ( C ₁ -C ₄₎ alkylamino, _((C 1 -C ₄₎ alkyl) _((C 1 -C ₄₎ alkyl) amino, _-CO 2 H, - O _{2 (C} 1 -C _{4) alkyl, -CONH 2, -CONH (C 1} -C 4) _{alkyl, -CON ((C 1 -C 4} ) alkyl) _((C 1 -C ₄₎ alkyl), - SO _{2 (C} 1 -C _{4) alkyl, -SO 2 NH 2, -SO 2} NH (C 1 -C 4) alkyl, and _{-SO 2 N ((C 1 -C} 4) alkyl) _{((C 1} - Optionally substituted by 1, 2 or 3 groups independently selected from C ₄ ) alkyl);
Or R ^a and R ^b together with the nitrogen to which they are attached represent a 5- to 8-membered saturated or unsaturated ring that may contain additional heteroatoms selected from oxygen, nitrogen, and sulfur, where The ring is (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl, amino, (C ₁ -C ₄ ) alkylamino, ((C ₁ -C ₄ ) alkyl) ((C ₁ -C ₄ ) 1, 2 or 3 groups independently selected from alkyl) amino, hydroxyl, oxo, (C ₁ -C ₄ ) alkoxy, and (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkyl Wherein the ring may be fused to a (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
Or R ^a and R ^b together with the nitrogen to which they are attached, a 6-10 membered bridged bicycle optionally fused to a (C ₃ -C ₈ ) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring Represents a formula ring system }. X and _Z, Ru is selected from the group consisting of _(C 1 -C _{8) alkyl, (C} 3 -C ₈₎ cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ^-NR a ^{R b,} and -OR ^a the pharmaceutical composition of claim 1. R ¹ _{is, (C} 1 -C _{8) alkyl, (C} 3 -C ₈₎ cycloalkyl or heterocycloalkyl, pharmaceutical composition according to claim 1 or 2,. X is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, trifluoromethyl, tetrahydropyran, hydroxymethyl, methoxymethyl, or benzyl;
Y is H;
Z is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or benzyl;
R ¹ is isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, (1-methylethyl) cyclopropyl, 1,1-dioxo-tetrahydrothiophen-3-yl, 1-Me-piperidin-4-yl, tetrahydrofuran- 3-yl, tetrahydropyran-4-yl, N, N-dimethyl-1-propanaminyl, benzyl, or 4-pyridyl;
R ³ is H, methyl, or Br; and R ⁶ is methyl, cyclopropyl, propyl, dimethylamino, ethylamino, (2-hydroxyethyl) amino, 2-propen-1-ylamino, 1-piperazinyl 1-piperidinyl, 4-morpholinyl, 4-piperidinylamino, tetrahydro-2H-pyran-4-ylamino, phenylamino , 2- (dimethylamino) ethyl] amino, 4-pyridinylamino, 4- (aminocarbonyl) phenyl Amino, 3-hydroxy-3-methyl-1-butyn-1-yl, 4-pyridinylethynyl, phenylethynyl, 2-furanyl, 3-thienyl; 1H-pyrazol-4-yl, 1H-indazole-5 -Yl, 1H-indazol-6-yl, 3-methyl-1H-indazole-5-i 1H-1,2,3-benzotriazol-5-yl, 2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 2-oxo-2,3-dihydro-1H-indole- 5-yl, 2-oxo-2,3-dihydro-1H-indol-6-yl, 2,1,3-benzoxadiazol-5-yl, 2-amino-6-quinazolinyl, 2,4-dioxo -1,2,3,4-tetrahydro-5-pyrimidinyl, 2-amino-5-pyrimidinyl, 7-oxo-1,5,6,7-tetrahydro-1,8-naphthyridin-3-yl, phenyl, 2 -Methylphenyl, 2-nitrophenyl, 2-phenylethyl, 3-aminophenyl, 4-aminophenyl, 4-chlorophenyl, 4-fluorophenyl, 4- (methyloxy) phenyl, 3- Acetylamino) phenyl, 4- (acetylamino) phenyl, 4- (aminocarbonyl) phenyl, 4- (1H-pyrazol-4-yl) phenyl, 4- (aminosulfonyl) phenyl, 4- (methylsulfonyl) phenyl, 4-[(dimethylamino) sulfonyl] phenyl, 4-[(methylamino) carbonyl] phenyl, 4-[(methylamino) sulfonyl] phenyl, 4-[(methylsulfonyl) amino] phenyl, 3-pyridinyl, 4- Pyridinyl, 2- (4-morpholinyl) -4-pyridinyl, 2-amino-4-pyridinyl, 5- (methyloxy) -3-pyridinyl, 5- (methylsulfonyl) -3-pyridinyl, 5-[(cyclopropyl Sulfonyl) amino] -6- (methyloxy) -3-pyridinyl, 5-[(phenyls Phonyl) amino] -3-pyridinyl, 6- (4-methyl-1-piperazinyl) -3-pyridinyl, 6- (4-morpholinyl) -3-pyridinyl, 6- (acetylamino) -3-pyridinyl, 6- (Dimethylamino) -3-pyridinyl, 6- (methyloxy) -3-pyridinyl, 6-[(methylamino) carbonyl] -3-pyridinyl, 6-[(methylamino) sulfonyl] -3-pyridinyl, 6- The pharmaceutical composition according to claim 1, which is methyl-3-pyridinyl or 4-pyridinyloxy. The compound of formula (I) is
  6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide;
  6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  6-Chloro-1- (1,1-dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyloxy) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-propen-1-ylamino) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  6-amino-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide;
  6-Cyclopropyl-1- (1-methylethyl) -N-[(4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinyl) methyl] -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide;
  6-cyclopropyl-1- (1-methylethyl) -N-{[6-methyl-4- (1-methylethyl) -2-oxo-1,2-dihydro-3-pyridinyl] methyl} -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  1- (1-Methylethyl) -N-[(4-Methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinyl) methyl] -6- (4-pyridinyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide;
  N-[(6-Ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide;
  1- (1-Methylethyl) -N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl) methyl] -6- (4-pyridinyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide;
  1- (1-Methylethyl) -N-{[6-Methyl-4- (1-methylethyl) -2-oxo-1,2-dihydro-3-pyridinyl] methyl} -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6-Cyclopropyl-1- (1-methylethyl) -N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl) methyl] -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide;
  1- (1-Methylethyl) -N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl) methyl] -6- (4-pyridinyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide;
  N-[(4-Cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide;
  N-[(4-Cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6-cyclopropyl-1- (1-methylethyl) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide;
  6-Cyclopropyl-1- (1-methylethyl) -N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl) methyl] -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide;
  N-[(4-Cyclopropyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6-cyclopropyl-N-[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(5-Fluoro-4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (ethylamino) -1- (1-methylethyl) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4- Carboxamide;
  6-Cyclopropyl-1- (1-methylethyl) -N-{[6-methyl-2-oxo-4- (trifluoromethyl) -1,2-dihydro-3-pyridinyl] methyl} -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- (Dimethylamino) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (1-piperidinyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-morpholinyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -6- [6- (4-methyl- 1-piperazinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (1-piperazinyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (3-hydroxy-3-methyl-1-butyn-1-yl) -1- ( 1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (3-methyl-1H-indazol-5-yl ) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (phenylethynyl) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-phenylethyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinylethynyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (phenylamino) -1H-pyrazolo [3,4 -B] pyridine-4-carboxamide;
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6-methyl-1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine -4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1,6-bis (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine -4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3,4-b] Pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (4-fluorophenyl) -1- (1-methylethyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide;
  6- {4-[(Dimethylamino) sulfonyl] phenyl} -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- [6- (Dimethylamino) -3-pyridinyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- {4-[(methylamino) sulfonyl] phenyl} -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- (4-Aminophenyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide;
  6- [4- (Acetylamino) phenyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- (3-Aminophenyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- {4-[(methylamino) carbonyl] phenyl} -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- [3- (acetylamino) phenyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl) -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- (2-Amino-4-pyridinyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- [4- (Aminosulfonyl) phenyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- {4-[(methylsulfonyl) amino] phenyl} -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- {4-[(Dimethylamino) sulfonyl] phenyl} -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1 -Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-piperidinylamino) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (tetrahydro-2H-pyran-4-ylamino)- 1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
6-{[2- (dimethylamino) ethyl] amino} -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl)- 1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6-[(2-hydroxyethyl) amino] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [5- (methyloxy) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [2- (methyloxy) -4-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- (6-Amino-3-pyridinyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [5- (methylsulfonyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (2-furanyl) -1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- {6-[(methylamino) carbonyl] -3-pyridinyl} -1- (1- Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- [5-[(Cyclopropylsulfonyl) amino] -6- (methyloxy) -3-pyridinyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) Methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- {5-[(phenylsulfonyl) amino] -3 -Pyridinyl} -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [2- (4-morpholinyl) -4-pyridinyl ] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [6- (4-morpholinyl) -3-pyridinyl ] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [6- (methyloxy) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- [6- (acetylamino) -3-pyridinyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-methylphenyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (1H-pyrazol-4-yl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- (2-Amino-5-pyrimidinyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (3-pyridinyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (1H-indazol-5-yl) -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- (1H-indazol-6-yl) -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- (1H-1,2,3-benzotriazol-5-yl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1 -Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -6- (2-oxo-2,3 -Dihydro-1H-benzimidazol-5-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-oxo-2,3-dihydro-1H -Indol-6-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-oxo-2,3-dihydro-1H -Indol-5-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-oxo-2,3-dihydro-1H -Benzimidazol-5-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [6- (4-methyl-1-piperazinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [6- (4-methyl-1-piperazinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -6- [6- (4-morpholinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinylamino) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-[(2-oxo-2,3-dihydro- 1H-benzimidazol-5-yl) amino] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6-{[4- (Aminocarbonyl) phenyl] amino} -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  1- (1,1-Dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- [6- (4- Methyl-1-piperazinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  1- (1,1-Dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- (2-oxo-2 , 3-dihydro-1H-benzimidazol-5-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  1- (1,1-Dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- [6- (4- Morpholinyl) -3-pyridinyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- (2,1,3-Benzoxadiazol-5-yl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl- 1- (1-methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- (2-Amino-6-quinazolinyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl ) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- {4-[(methylamino) sulfonyl] phenyl} -1- (1 -Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- [4- (Acetylamino) phenyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl ) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6- [4- (Aminocarbonyl) phenyl] -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (7-oxo-1,5,6,7- Tetrahydro-1,8-naphthyridin-3-yl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6- {6-[(methylamino) sulfonyl] -3-pyridinyl} -1- (1- Methylethyl) -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  1- (2-Aminoethyl) -6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1H-pyrazolo [3,4-b ] Pyridine-4-carboxamide;
  6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- {2-[(methylsulfonyl) amino] ethyl} -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -6-methyl-1- (phenylmethyl) -1H-pyrazolo [3,4-b] pyridine- 4-carboxamide;
  6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1-ethyl-1H-pyrazolo [3,4-b] pyridine-4- Carboxamide;
  6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1-propyl-1H-pyrazolo [3,4-b] pyridine-4- Carboxamide;
  6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide;
1-Cyclobutyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [3,4-b] pyridine -4-carboxamide;
  1-cyclopentyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [3,4-b] Pyridine-4-carboxamide;
  6-Cyclopropyl-1- (1,1-dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (4-pyridinyl) -1H-pyrazolo [3,4-b] Pyridine-4-carboxamide;
  6-cyclopropyl-1- (1-cyclopropylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [ 3,4-b] pyridine-4-carboxamide;
  1-cyclohexyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [3,4-b] Pyridine-4-carboxamide;
  6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methyl-4-piperidinyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  6-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (tetrahydro-2H-pyran-4-yl)- 1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [4- (methyloxy) phenyl] -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (4-pyridinyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  6- (4-Chlorophenyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (3-thienyl) -1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1- (1-methylethyl) -6- (4-pyridinyl) -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  1,6-bis (1,1-dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [4- (methylsulfonyl) phenyl] -1H- Pyrazolo [3,4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- [4- (1H-pyrazol-4-yl) Phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  1- (1,1-Dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- [4- (methyloxy ) Phenyl] -1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  1- (1,1-Dimethylethyl) -N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -3-methyl-6- (3-pyridinyl)- 1H-pyrazolo [3,4-b] pyridine-4-carboxamide;
  3-Bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-phenyl-1H-pyrazolo [3 4-b] pyridine-4-carboxamide;
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6- (2-nitrophenyl) -1H-pyrazolo [3 , 4-b] pyridine-4-carboxamide;Or
  N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl) methyl] -1- (1-methylethyl) -6-propyl-1H-pyrazolo [3,4-b] The pyridine-4-carboxamide according to claim 1, which is pyridine-4-carboxamide.Pharmaceutical composition. The cancer is brain cancer, glioblastoma, leukemia, lymphoma, Banayan-Zonana syndrome, Cowden disease, Lermit-Ducro disease, breast cancer, inflammatory breast cancer, Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, marrow Blastoma, colon cancer, stomach cancer, bladder cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, kidney cancer, ovarian cancer, pancreatic cancer, prostate cancer, non-epithelial malignant tumor, osteosarcoma, bone giant cell tumor, The pharmaceutical composition according to any one of claims 1 to 5, which is selected from the group consisting of thyroid cancer and thyroid cancer.